1-arylcarbonyl-4-oxy-piperidine compounds useful for the treatment of neurodegenerative diseases

ABSTRACT

The present invention provides a compound useful as an agent for the prophylaxis or treatment of neurodegenerative disease and the like, or a salt thereof. 
     The present invention relates to a compound represented by the formula 
                         
wherein each symbol is as defined in the specification, or a salt thereof.

TECHNICAL FIELD

The present invention relates to a heterocyclic compound having acholesterol 24-hydroxylase (in the present specification, sometimes tobe abbreviated as “CH24H”) inhibitory action, pharmaceutical compositioncomprising same, and the like.

BACKGROUND OF THE INVENTION

Alzheimer's disease is a progressive neurodegenerative diseasecharacterized by the deposition of amyloid β protein (Ar), accumulationof phosphorylated tau in a nerve cell (neurofibrillary tangle), andnerve cell death. In recent years, the number of patients with Alzheimeris increasing because of aging, but an effective treatment method hasnot been developed as yet. The therapeutic drugs for Alzheimer's diseasewhich are currently used in the medical front are mainlyacetylcholinesterase (AchE) inhibitors. While AchE inhibitors provide acertain, confirmed level of usefulness, since they aim to supplementdepressed acetylcholine, the treatment with AchE inhibitor is merely asymptomatic therapy. Thus, the prompt development of a basic remedy andprophylactic drug has been strongly desired.

It has been clarified that the presence of allele ε4 of apolipoprotein E(ApoE) controlling the cholesterol metabolism is a strong risk factor ofAlzheimer's disease [non-patent document 1: Science, vol. 261, 921-923,1993]. After this finding, the correlation between plural genepolymorphisms bearing the expression of protein controlling thecholesterol metabolism and the onset frequency of Alzheimer's diseasehas been shown, suggesting the correlation between the cholesterolmetabolism and Alzheimer's disease [non-patent document 2: Neurobiol.Aging, vol. 24, 421-426, 2003, non-patent document 3: Mol. Psychiatry,vol. 8, 635-638, 2003]. Moreover, it has been reported that Cyp46 (sameas “cholesterol 24-hydroxylase (CH24H)”), which is cholesterol oxidasespecifically expressed in the brain, is a risk factor of Alzheimer'sdisease [non-patent document 4: Neurosci. Lett., vol. 328, pages 9-12,2002]. Furthermore, it has also been reported that Cyp46(CH24H) isexpressed in periphery of deposited amyloid in Alzheimer patients[non-patent document 5: J. Biol. Chem., vol. 279, pages 34674-34681,2004], 24S-hydroxycholesterol (24-HC), which is a metabolite thereof,increases in the brain spinal cord fluid (CSF) of Alzheimer patients[non-patent document 6: Neurosci. Lett., vol. 324, pages 83-85, 2002,non-patent document 7: Neurosci. Lett., vol. 397, pages 83-87, 2006] andthat 24-HC induces cell death of SH-SY5Y cell, which is a humanneuroblast line [non-patent document 8: Brain Res., vol. 818, pages171-175, 1999], and rats treated with 24-HC into the cerebral ventricleshowed impaired short-term memory, which is commonly observed inAlzheimer's disease, suggesting that hippocampal neurons were damaged by24-HC [non-patent document 9: Neuroscience, vol. 164, pages 398-403,2009]. These findings suggest that Cyp46(CH24H) is deeply involved inthe pathology of Alzheimer's disease. Therefore, a compound thatinhibits the activity of Cyp46 (CH24H) (i.e., Cyp46(CH24H) inhibitor)suppresses nerve cell death, Aβ increase, intracerebral inflammation andthe like observed in Alzheimer's disease, by decreasing intracerebral24-HC, and is promising as a therapeutic or prophylactic drug showingnot only an improvement of symptom but also a suppression ofprogression. Moreover, it has been reported that AchE inhibitorclinically used as a therapeutic drug for Alzheimer's disease shows animproving effect on memory disorders induced by Aβ in mouse [non-patentdocument 10: British Journal of Pharmacology, vol. 149, pages 998-1012,2006], and Cyp46(CH24H) inhibitor showing an improvement effect formemory disorders in Aβ overexpression animal model (APP transgenicmouse, APP/PS1 double transgenic mouse etc.) is promising as atherapeutic drug for Alzheimer's disease.

As a concept of the prestage of Alzheimer's disease, a mild cognitiveimpairment has been proposed, and about half of those having thisdisorder is said to progress into the Alzheimer's disease in the future.In recent years, it has been reported that 24-HC increases not only inpatients with Alzheimer's disease but also in CSF of patients with mildcognitive impairment [non-patent document 7: Neurosci. Lett., vol. 397,pages 83-87, 2006]. This finding suggests that Cyp46(CH24H) is involvedin the pathology of mild cognitive impairment, and therefore, aCyp46(CH24H) inhibitor is promising as a new therapeutic drug forAlzheimer's disease or a prophylactic drug for the progression into theAlzheimer's disease.

In recent years, moreover, it has been reported that 24-HC in the bloodincreases before expression of the symptom in an autoimmuneencephalomyelitis model, which is an animal model of multiple sclerosiswhich is one of the demyelination diseases in the central nervous system[non-patent document 11: J. Neurosci. Res., vol. 85, pages 1499-1505,2007]. Multiple sclerosis is often developed in younger people of about30 years old, and scarcely developed in the elderly of 60 years orolder. It has also been reported that 24-HC increases in multiplesclerosis patients aging from 21 to 50 [non-patent document 12:Neurosci. Lett., vol. 331, pages 163-166, 2002]. These findings suggestthat Cyp46(CH24H) is involved in the pathology of multiple sclerosis,and therefore, Cyp46(CH24H) inhibitor is promising as a new therapeuticor prophylactic drug for multiple sclerosis.

Traumatic brain injury (also referred to as TBI in the presentspecification) is a condition exerting an extremely harmful influence onthe health of individual, for which no effective cure has beenestablished. In the repair process following tissue damage in TBI,reconstruction of nerve cell membrane and distribution of intracerebralcholesterol activated along with the growth of glial cell are suggested[non-patent document 13: Proc. Natl. Acad. Sci. USA, vol. 102, pages8333-8338, 2005]. In a rat TBI model, an enhanced expression ofCyp46(CH24H) after trauma has been reported [non-patent document 14: J.Neurotrauma, vol. 25, pages 1087-1098, 2008]. Moreover, it has also beenreported that 24-HC injures nerve cells [non-patent document 8: BrainRes., vol. 818, pages 171-175, 1999], and therefore, Cyp46(CH24H)inhibitor is promising as a new therapeutic or prophylactic drug forTBI.

As a pathological significance of 24-HC in neurodegenerative diseases,an inflammatory gene expression-enhancing action in nerve cells has beenreported [non-patent document 15: NeuroReport, vol. 16, pages 909-913,2005]. In addition, it is suggested that an intracerebral inflammationreaction accompanied by activation of glial cell is a pathologicalchange characteristic of neurodegenerative diseases [non-patent document16: Glia, vol. 50, pages 427-434, 2005]. In recent years, a therapeuticeffect by suppression of intracerebral inflammation has also beenreported for neurodegenerative diseases such as Huntington's disease,Parkinson's disease and amyotrophic lateral sclerosis and the like[non-patent document 17: Mol. Neurodegeneration, vol. 4, pages 47-59,2009]. Therefore, suppression of intracerebral inflammation bydecreasing 24-HC by the inhibition of Cyp46(CH24H) is promising as a newtherapeutic or prophylactic drug for neurodegenerative diseases such asHuntington's disease, Parkinson's disease, cerebral infarction,glaucoma, amyotrophic lateral sclerosis and the like.

Glaucoma is the main cause of blindness, and is considered a serioussocial problem. However, normal intraocular pressure type fieldstenosis, which is the major symptom of the disease, has no effectivecure. In recent years, it has also been reported that gene polymorphismof Cyp46(CH24H) associated with high blood 24-HC is related to the riskof the onset of glaucoma [non-patent document 18: Invest. Ophthalmol.Vis. Sci., vol. 50, pages 5712-5717, 2009], and Cyp46(CH24H) inhibitoris promising as a therapeutic or prophylactic drug for glaucoma.

Spasm is a disease that occurs in fits along with abnormal electricexcitement of intracerebral nerve cells. Spasm is also one of thecharacteristic clinical findings in Alzheimer's disease [non-patentdocument 19: Epilepsia, vol. 47, pages 867-872, 2006], and it has beenreported that spasm is highly frequently developed in APP/PS1 doubletransgenic mouse which is one kind of Alzheimer's disease models due toAβ overexpression [non-patent document 20: J. Neurosci., vol. 29, pages3453-3462, 2012]. It has been reported that carbamazepine, which is atherapeutic drug for spasm, shows a short term memory improving effectin a Y-maze test using mouse spasm model [non-patent document 21: J.Neurol. Neurosurg. Psychiatry, vol. 48, pages 459-468, 1985]. Thus, inanimal model with spasm symptoms, Cyp46(CH24H) inhibitor showing a shortterm memory improving effect is promising as a therapeutic orprophylactic drug for spasm.

Since schizophrenia shows a variety of psychological symptoms such ashallucination, delusion, excitation, manic-depressive state and thelike, therapeutic drugs therefor have been developed from variousangles. In recent years, it has been pointed out that changes in thecholesterol metabolism are involved in the abnormality of neuralactivity seen in schizophrenia [non-patent document 22: J. PsychiatryNeurosci., vol. 36, pages 47-55, 2011]. Since cytotoxic factors such asoxidative stress also contribute to the pathology of schizophrenia,nerve cell toxicity due to 24-HC may aggravate the symptoms [non-patentdocument 23: Psychoneuroendocrinology, vol. 28, pages 83-96, 2003].Therefore, Cyp46(CH24H) inhibitor that inhibits metabolism ofcholesterol into 24-HC in the brain is promising as a new therapeutic orprophylactic drug for schizophrenia.

Examples of the compound having a structure similar to the presentcompound include the following compounds.

Patent document 1 discloses the following compound:

whereinX₁, X₂ and X₃ are independently N, O, S, C or the like;G₁ is CR_(a)R_(b), NR₇, or optionally substituted nitrogen-containingheterocycloalkyl;G₂ is a single bond, optionally substituted alkyl or the like;R₁ is aryl, nitrogen-containing heteroaryl or the like;R₂ is optionally substituted alkyl, optionally substituted aryl,optionally substituted heteroaryl or the like;R₃ and R₄ are independently H, halogen, optionally substituted alkyl orthe like;R₅, R₆, R₇ and R₈ are independently H, halogen, optionally substitutedalkyl or the like;R₅ and R₆ in combination optionally form oxo; andR_(a) and R_(b) are independently H, halogen, optionally substitutedalkyl or the like,as an agent for the treatment of inflammation disease, Alzheimer'sdisease and the like.

Patent document 2 discloses the following compound:

whereinV is carbonyl or the like;A is N or C(H);R¹ is H, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl or the like;R², R^(2a), R³, R^(3a), R⁴, R^(4a), R⁵ and R^(5a) are independently H,halogen, optionally substituted alkyl or the like;R⁶ is —R⁸—OR¹⁰, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted aryl, optionally substitutedheterocycloalkyl, optionally substituted heteroaryl or the like;R⁸ is a single bond, alkynylene or alkenylene; andR⁹ and R¹⁰ are independently H, halogen, optionally substituted alkyl orthe like,as an agent for the treatment of autoimmune diseases, Alzheimer'sdisease, age-related dementia and the like.

Patent document 3 discloses the following compound:

whereinA-B is N—O, O—N or N(H)—N;R¹ is H, C₁₋₈ alkyl, C₁₋₈ alkoxy, hydroxy, halogen or the like;R² is H, aryl, heteroaryl, C₁₋₆ alkyl or the like;Q is a nitrogen-containing ring (the following formula (IIb) etc.)

R⁶ is H, hydroxy, aryl or the like;X, Y and Z are independently O, NR⁷ or CR⁷ ₂;R⁷ is, H, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₁₋₄ alkoxy, heteroaryl-C₁₋₆ alkyl,aryl-C₁₋₆ alkyl or the like; andn is 0-3,as an agent for the treatment of diseases associated with immunedisease, dementia, hypertension, diabetes and the like (e.g.,Alzheimer's disease etc.)

Patent document 4 discloses the following compound:

whereinHt is a heterocyclic group (pyrrol-3-yl, [1,2,4]triazol-3-yl,[1,2,3]triazol-4-yl or tetrazol-5-yl, the pyrrol-3-yl has R³ and Qn-R⁴,and the [1,2,4]triazol-3-yl or [1,2,3]triazol-4-yl has R³ or Qn-R⁴);T and Q are independently —C(O)— or the like;m and n are independently 0-1;R² is R or the like;R³ is R⁷, halogen, cyano or the like;R is a C₁₋₆ hydrocarbon group, C₆₋₁₀ aryl, C₆₋₁₀ heteroaryl, C₃₋₁₀heterocycloalkyl or the like; andR⁷ is H, an optionally substituted C₁₋₆ hydrocarbon group or the like,as an agent for the treatment of autoimmune diseases, Alzheimer'sdisease and the like.

DOCUMENT LIST Patent Document

-   Patent Document 1: WO 2009/117421-   Patent Document 2: WO 2008/134547-   Patent Document 3: WO 2008/011453-   Patent Document 4: WO 02/088097

Non-Patent Document

-   Non-Patent Document 1: Science, vol. 261, 921-923, 1993-   Non-Patent Document 2: Neurobiol. Aging, vol. 24, 421-426, 2003-   Non-Patent Document 3: Mol. Psychiatry, vol. 8, 635-638, 2003-   Non-Patent Document 4: Neurosci. Lett., vol. 328, pages 9-12, 2002-   Non-Patent Document 5: J. Biol. Chem., vol. 279, pages 34674-34681,    2004-   Non-Patent Document 6: Neurosci. Lett., vol. 324, pages 83-85, 2002-   Non-Patent Document 7: Neurosci. Lett., vol. 397, pages 83-87,-   Non-Patent Document 8: Brain Res., vol. 818, pages 171-175, 1999-   Non-Patent Document 9: Neuroscience, vol. 164, pages 398-403, 2009-   Non-Patent Document 10: British Journal of Pharmacology, vol. 149,    pages 998-1012, 2006-   Non-Patent Document 11: J. Neurosci. Res., vol. 85, pages 1499-1505,    2007-   Non-Patent Document 12: Neurosci. Lett., vol. 331, pages 163-166,    2002-   Non-Patent Document 13: Proc. Natl. Acad. Sci. USA, vol. 102, pages    8333-8338, 2005-   Non-Patent Document 14: J. Neurotrauma, vol. 25, pages 1087-1098,    2008-   Non-Patent Document 15: NeuroReport, vol. 16, pages 909-913, 2005-   Non-Patent Document 16: Glia, vol. 50, pages 427-434, 2005-   Non-Patent Document 17: Mol. Neurodegeneration, vol. 4, pages 47-59,    2009-   Non-Patent Document 18: Invest. Opthalmol. Vis. Sci., vol. 50, pages    5712-5717, 2009-   Non-Patent Document 19: Epilepsia, vol. 47, pages 867-872, 2006-   Non-Patent Document 20: J. Neurosci., vol. 29, pages 3453-3462, 2012-   Non-Patent Document 21: J. Neurol. Neurosurg. Psychiatry, vol. 48,    pages 459-468, 1985-   Non-Patent Document 22: J. Psychiatry Neurosci., vol. 36, pages    47-55, 2011-   Non-Patent Document 23: Psychoneuroendocrinology, vol. 28, pages    83-96, 2003

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

An object of the present invention is to provide a compound having asuperior CH24H inhibitory action, which is useful as an agent for theprophylaxis or treatment of neurodegenerative disease (e.g., Alzheimer'sdisease, mild cognitive impairment, Huntington's disease, Parkinson'sdisease, amyotrophic lateral sclerosis, traumatic brain injury, cerebralinfarction, glaucoma, multiple sclerosis and the like), epilepsy,schizophrenia and the like.

Means of Solving the Problems

The present inventors have conducted intensive studies in an attempt tosolve the above-mentioned problem and found that a compound representedby the following formula (I) has a superior CH24H inhibitory action,which resulted in the completion of the present invention.

Accordingly, the present invention provides the following.

[1] A compound represented by the formula (I):

whereinR¹ is an optionally substituted C₁₋₆ alkyl group;R² is a hydrogen atom or an optionally substituted C₁₋₆ alkyl group;R³ is an optionally substituted 5- or 6-membered aromatic heterocyclicgroup;ring A is a further optionally substituted piperidine ring (thepiperidine ring is optionally bridged); and ring B is a furtheroptionally substituted 5- or 6-membered aromatic ring (X and Y areindependently a carbon atom or a nitrogen atom),or a salt thereof.[2] The compound or salt of the above-mentioned [1], wherein R³ is anoptionally substituted 5- or 6-membered nitrogen-containing aromaticheterocyclic group.[3] The compound or salt of the above-mentioned [1], wherein R³ is a 5-or 6-membered nitrogen-containing aromatic heterocyclic group optionallysubstituted by 1 to 3 halogen atoms.[4] The compound or salt of the above-mentioned [1], wherein R³ is agroup represented by

whereinring C¹ is an optionally substituted 6-membered nitrogen-containingaromatic heterocycle containing at least one nitrogen atom; andring C² is an optionally substituted 5-membered nitrogen-containingaromatic heterocycle containing at least one nitrogen atom,each of which is optionally substituted by 1 to 3 halogen atoms.[5] The compound or salt of the above-mentioned [1], wherein ring B isbenzene, thiazole, isoxazole, pyrazole, pyridine or pyrazine (X and Yare independently a carbon atom or a nitrogen atom), each of which is,in addition to R³ and —C(═O)— ring A, optionally substituted by 1 to 3substituents selected from(1) a halogen atom,(2) a C₁₋₆ alkyl group optionally substituted by 1 to 3 halogen atoms,(3) a C₁₋₆ alkoxy group, and(4) a C₁₋₆ alkylenedioxy group.[6] The compound or salt of the above-mentioned [1], wherein ring B is

each of which is, in addition to R³ and —C(═O)-ring A, optionallysubstituted by 1 to 3 substituents selected from

-   -   (1) a halogen atom,    -   (2) a C₁₋₆ alkyl group optionally substituted by 1 to 3 halogen        atoms,    -   (3) a C₁₋₆ alkoxy group, and    -   (4) a C₁₋₆ alkylenedioxy group.        [7] The compound or salt of the above-mentioned [1], wherein R²        is a hydrogen atom.        [8] The compound or salt of the above-mentioned [1], wherein R¹        is a C₁₋₆ alkyl group optionally substituted by 1 to 3        substituents selected from    -   (1) a C₆₋₁₄ aryl group optionally substituted by 1 to 3        substituents selected from        -   (a) a halogen atom,        -   (b) a cyano group, and        -   (c) a C₁₋₆ alkoxy group optionally substituted by 1 to 3            halogen atoms    -   (2) a 5- or 6-membered monocyclic aromatic heterocyclic group        optionally substituted by 1 to 3 substituents selected from        -   (a) a halogen atom,        -   (b) a cyano group, and        -   (c) a C₁₋₆ alkoxy group optionally substituted by 1 to 3            halogen atoms, and    -   (3) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group optionally substituted by 1 to 3 substituents selected        from        -   (a) a halogen atom,        -   (b) a cyano group, and        -   (c) a C₁₋₆ alkoxy group optionally substituted by 1 to 3            halogen atoms;            R² is a hydrogen atom or a C₁₋₆ alkyl group;            R³ is a 5- or 6-membered nitrogen-containing aromatic            heterocyclic group optionally substituted by 1 to 3 halogen            atoms;            ring A is a piperidine ring having no substituent other than            R¹, R²—O— and —C(═O)-ring B, or an            oxa-9-azabicyclo[3.3.1]nonane ring having no substituent            other than R¹, R²—O— and —C(═O)-ring B; and            ring B is a 5- or 6-membered aromatic ring which is, in            addition to R³ and —C(═O)— ring A, optionally substituted by            1 to 3 substituents selected from    -   (1) a halogen atom,    -   (2) a C₁₋₆ alkyl group optionally substituted by 1 to 3 halogen        atoms,    -   (3) a C₁₋₆ alkoxy group and    -   (4) a C₁₋₆ alkylenedioxy group.        [9] (4-benzyl-4-hydroxypiperidin-1-yl)        (2,4′-bipyridin-3-yl)methanone or a salt thereof.        [10]        2,4′-bipyridin-3-yl(4-(4-fluorobenzyl)-4-hydroxypiperidin-1-yl)methanone        or a salt thereof.        [11]        2,4′-bipyridin-3-yl(4-(2,4-difluorobenzyl)-4-hydroxypiperidin-1-yl)methanone        or a salt thereof.        [12] (4-(4-fluorobenzyl)-4-hydroxypiperidin-1-yl)        (2-(pyrimidin-4-yl)pyridin-3-yl)methanone or a salt thereof.        [13] A medicament comprising the compound or salt of the        above-mentioned [1].        [14] The medicament of the above-mentioned [13], which is a        cholesterol 24-hydroxylase inhibitor.        [15] The medicament of the above-mentioned [13], which is an        agent for the prophylaxis or treatment of neurodegenerative        disease.        [16] The medicament of the above-mentioned [15], wherein the        neurodegenerative disease is Alzheimer's disease, mild cognitive        impairment, Huntington's disease, Parkinson's disease or        multiple sclerosis.        [17] The compound or salt of the above-mentioned [1] for use in        the prophylaxis or treatment of neurodegenerative disease.        [18] The compound or salt of the above-mentioned [17], wherein        the neurodegenerative disease is Alzheimer's disease, mild        cognitive impairment, Huntington's disease, Parkinson's disease        or multiple sclerosis.        [19] A method of inhibiting a cholesterol 24-hydroxylase in a        mammal, which comprises administering an effective amount of the        compound or salt of the above-mentioned [1] to a mammal.        [20] A method for the prophylaxis or treatment of        neurodegenerative disease in a mammal, which comprises        administering an effective amount of the compound or salt of the        above-mentioned [1] to a mammal.        [21] The method of the above-mentioned [20], wherein the        neurodegenerative disease is Alzheimer's disease, mild cognitive        impairment, Huntington's disease, Parkinson's disease or        multiple sclerosis.        [22] Use of the compound or salt of the above-mentioned [1] for        the production of an agent for the prophylaxis or treatment of        neurodegenerative disease.        [23] Use of the above-mentioned [22], wherein the        neurodegenerative disease is Alzheimer's disease, mild cognitive        impairment, Huntington's disease, Parkinson's disease or        multiple sclerosis.

Effect of the Invention

Compound (I) has a superior CH24H inhibitory action, which is useful asan agent for the prophylaxis or treatment of neurodegenerative disease(e.g., Alzheimer's disease, mild cognitive impairment, Huntington'sdisease, Parkinson's disease, amyotrophic lateral sclerosis, traumaticbrain injury, cerebral infarction, glaucoma, multiple sclerosis and thelike), epilepsy, schizophrenia and the like.

DETAILED DESCRIPTION OF THE INVENTION

In the present specification, the “halogen atom” means a fluorine atom,a chlorine atom, a bromine atom or an iodine atom.

In the present specification, the “C₁₋₆ alkyl (group)” means, forexample, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl,isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl,2-ethylbutyl or the like.

In the present specification, the “C₂₋₆ alkenyl (group)” means, forexample, vinyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl,2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl,5-hexenyl or the like.

In the present specification, the “C₂₋₆ alkynyl (group)” means, forexample, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl,3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl,1,1-dimethylprop-2-yn-1-yl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl,5-hexynyl or the like.

In the present specification, the “C₁₋₆ alkoxy (group)” means, forexample, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, hexyloxy or the like.

In the present specification, the “C₂₋₆ alkenyloxy (group)” means, forexample, vinyloxy, 1-propenyloxy, 2-propenyloxy, 2-methyl-1-propenyloxy,1-butenyloxy, 2-butenyloxy, 3-butenyloxy, 3-methyl-2-butenyloxy,1-pentenyloxy, 2-pentenyloxy, 3-pentenyloxy, 4-pentenyloxy,4-methyl-3-pentenyloxy, 1-hexenyloxy, 3-hexenyloxy, 5-hexenyloxy or thelike.

In the present specification, the “C₂₋₆ alkynyloxy (group)” means, forexample, ethynyloxy, 1-propynyloxy, 2-propynyloxy, 1-butynyloxy,2-butynyloxy, 3-butynyloxy, 1-pentynyloxy, 2-pentynyloxy, 3-pentynyloxy,4-pentynyloxy, 1,1-dimethylprop-2-yn-1-yloxy, 1-hexynyloxy,2-hexynyloxy, 3-hexynyloxy, 4-hexynyloxy, 5-hexynyloxy or the like.

In the present specification, the “C₁₋₆ alkylenedioxy (group)” means,for example, methylenedioxy, ethylenedioxy or the like.

In the present specification, the “C₁₋₆ alkoxy-carbonyl (group)” means,for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,tert-butoxycarbonyl or the like.

In the present specification, the “C₁₋₆ alkyl-carbonyl (group)” means,for example, acetyl, propanoyl, butanoyl, 2-methylpropanoyl or the like.

In the present specification, the “mono-C₁₋₆ alkylamino (group)” means,for example, methylamino, ethylamino, propylamino, isopropylamino,butylamino, isobutylamino, tert-butylamino or the like.

In the present specification, the “di-C₁₋₆ alkylamino (group)” means,for example, dimethylamino, diethylamino, dipropylamino,diisopropylamino, dibutylamino, diisobutylamino, di-tert-butylamino orthe like.

In the present specification, the “C₃₋₈ cycloalkyl (group)” means, forexample, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl or the like.

In the present specification, the “C₃₋₆ cycloalkyl (group)” means, forexample, cycloalkyl having 3 to 6 carbon atoms, from among theabove-mentioned C₃₋₈ cycloalkyl (group). In the present specification,the “C₃₋₈ cycloalkyloxy (group)” means, for example, cyclopropyloxy,cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy,cyclooctyloxy or the like.

In the present specification, the “C₃₋₆ cycloalkyloxy (group)” means,for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy,cyclohexyloxy or the like.

In the present specification, the “C₃₋₈ cycloalkenyl (group)” means, forexample, cyclopropenyl (e.g., 2-cyclopropen-1-yl), cyclobutenyl (e.g.,2-cyclobuten-1-yl), cyclopentenyl (e.g., 2-cyclopenten-1-yl,3-cyclopenten-1-yl), cyclohexenyl (e.g., 2-cyclohexen-1-yl,3-cyclohexen-1-yl) or the like.

In the present specification, the “C₃₋₈ cycloalkenyloxy (group)” means,for example, cyclopropenyloxy (e.g., 2-cyclopropen-1-yloxy),cyclobutenyloxy (e.g., 2-cyclobuten-1-yloxy), cyclopentenyloxy (e.g.,2-cyclopenten-1-yloxy, 3-cyclopenten-1-yloxy), cyclohexenyloxy (e.g.,2-cyclohexen-1-yloxy, 3-cyclohexen-1-yloxy) or the like.

In the present specification, the “C₆₋₁₄ aryl (group)” means, forexample, phenyl, 1-naphthyl, 2-naphthyl or the like. In the presentspecification, the “C₆₋₁₄ aryloxy (group)” means, for example, phenoxy,1-naphthyloxy, 2-naphthyloxy or the like.

In the present specification, the “C₇₋₁₄ aralkyl (group)” means, forexample, benzyl, phenethyl or the like.

In the present specification, the “C₇₋₁₄ aralkyloxy (group)” means, forexample, benzyloxy, phenethyloxy or the like.

In the present specification, the “heterocyclic group” means an aromaticheterocyclic group or a non-aromatic heterocyclic group.

In the present specification, the “aromatic heterocyclic group” means amonocyclic aromatic heterocyclic group or a fused aromatic heterocyclicgroup.

In the present specification, examples of the “monocyclic aromaticheterocyclic group” include a 5- to 7-membered (preferably 5- or6-membered) monocyclic aromatic heterocyclic group containing, as aring-constituting atom besides carbon atoms, 1 to 4 hetero atomsselected from an oxygen atom, a sulfur atom (optionally oxidized) and anitrogen atom (optionally oxidized). Examples thereof include furyl(e.g., 2-furyl, 3-furyl), thienyl (e.g., 2-thienyl, 3-thienyl), pyridyl(e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (e.g.,2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (e.g.,3-pyridazinyl, 4-pyridazinyl), pyrazinyl (e.g., 2-pyrazinyl), pyrrolyl(e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (e.g.,1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), pyrazolyl(e.g., 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), thiazolyl (e.g.,2-thiazolyl, 4-thiazolyl, 5-thiazolyl), isothiazolyl (e.g.,3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), oxazolyl (e.g.,2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (e.g., 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (e.g., 1,2,4-oxadiazol-5-yl,1,3,4-oxadiazol-2-yl), thiadiazolyl (e.g., 1,3,4-thiadiazol-2-yl),triazolyl (e.g., 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl,1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl), tetrazolyl(e.g., tetrazol-1-yl, tetrazol-5-yl), triazinyl (e.g.,1,2,4-triazin-1-yl, 1,2,4-triazin-3-yl) and the like.

In the present specification, examples of the “fused aromaticheterocyclic group” include a 8- to 12-membered fused aromaticheterocyclic group, specifically, a group derived from a fused ringwherein a ring corresponding to the 5- to 7-membered monocyclic aromaticheterocyclic group is fused with a C₆₋₁₄ aromatic hydrocarbon; and agroup derived from a fused ring wherein rings corresponding to the 5- to7-membered monocyclic aromatic heterocyclic groups are fused. Examplesthereof include quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl,6-quinolyl), isoquinolyl (e.g., 3-isoquinolyl), quinazolyl (e.g.,2-quinazolyl, 4-quinazolyl), quinoxalyl (e.g., 2-quinoxalyl,6-quinoxalyl), benzofuranyl (e.g., 2-benzofuranyl, 3-benzofuranyl),benzothienyl (e.g., 2-benzothienyl, 3-benzothienyl), benzoxazolyl (e.g.,2-benzoxazolyl), benzisoxazolyl (e.g., 7-benzisoxazolyl), benzothiazolyl(e.g., 2-benzothiazolyl), benzimidazolyl (e.g., benzimidazol-1-yl,benzimidazol-2-yl, benzimidazol-5-yl), benzotriazolyl (e.g.,1H-1,2,3-benzotriazol-5-yl), indolyl (e.g., indol-1-yl, indol-2-yl,indol-3-yl, indol-5-yl), indazolyl (e.g., 1H-indazol-3-yl),pyrrolopyrazinyl (e.g., 1H-pyrrolo[2,3-b]pyrazin-2-yl,1H-pyrrolo[2,3-b]pyrazin-6-yl), imidazopyridyl (e.g.,1H-imidazo[4,5-b]pyridin-2-yl, 1H-imidazo[4,5-c]pyridin-2-yl,2H-imidazo[1,2-a]pyridin-3-yl), thienopyridyl (e.g.,thieno[2,3-b]pyridin-3-yl), imidazopyrazinyl (e.g.,1H-imidazo[4,5-b]pyrazin-2-yl), pyrazolopyridyl (e.g.,1H-pyrazolo[4,3-c]pyridin-3-yl), pyrazolothienyl (e.g.,2H-pyrazolo[3,4-b]thiophen-2-yl), pyrazolotriazinyl (e.g.,pyrazolo[5,1-c] [1,2,4]triazin-3-yl) and the like.

In the present specification, the “non-aromatic heterocyclic group”means a monocyclic non-aromatic heterocyclic group or a fusednon-aromatic heterocyclic group.

In the present specification, examples of the “monocyclic non-aromaticheterocyclic group” include a 3- to 8-membered (preferably 5- or6-membered) monocyclic non-aromatic heterocyclic group containing, as aring-constituting atom besides carbon atoms, 1 to 4 hetero atomsselected from an oxygen atom, a sulfur atom (optionally oxidized) and anitrogen atom (optionally oxidized). Examples thereof include azetidinyl(e.g., 1-azetidinyl, 2-azetidinyl), pyrrolidinyl (e.g., 1-pyrrolidinyl,2-pyrrolidinyl), piperidyl (e.g., piperidino, 2-piperidyl, 3-piperidyl,4-piperidyl), morpholinyl (e.g., morpholino), thiomorpholinyl (e.g.,thiomorpholino), piperazinyl (e.g., 1-piperazinyl, 2-piperazinyl,3-piperazinyl), oxazolidinyl (e.g., oxazolidin-2-yl), thiazolidinyl(e.g., thiazolidin-2-yl), dihydrothiopyranyl (e.g.,dihydrothiopyran-3-yl, dihydrothiopyran-4-yl), imidazolidinyl (e.g.,imidazolidin-2-yl, imidazolidin-3-yl), oxazolinyl (e.g., oxazolin-2-yl),thiazolinyl (e.g., thiazolin-2-yl), imidazolinyl (e.g., imidazolin-2-yl,imidazolin-3-yl), dioxolyl (e.g., 1,3-dioxol-4-yl), dioxolanyl (e.g.,1,3-dioxolan-4-yl), dihydrooxadiazolyl (e.g.,4,5-dihydro-1,2,4-oxadiazol-3-yl), pyranyl (e.g., 2-pyranyl, 4-pyranyl),tetrahydropyranyl (e.g., 2-tetrahydropyranyl, 3-tetrahydropyranyl,4-tetrahydropyranyl), thiopyranyl (e.g., 4-thiopyranyl),tetrahydrothiopyranyl (e.g., 2-tetrahydrothiopyranyl,3-tetrahydrothiopyranyl, 4-tetrahydrothiopyranyl),1-oxidotetrahydrothiopyranyl (e.g., 1-oxidotetrahydrothiopyran-4-yl),1,1-dioxidotetrahydrothiopyranyl (e.g.,1,1-dioxidotetrahydrothiopyran-4-yl), tetrahydrofuryl (e.g.,tetrahydrofuran-3-yl, tetrahydrofuran-2-yl), oxetanyl (e.g.,oxetan-2-yl, oxetan-3-yl), pyrazolidinyl (e.g., pyrazolidin-1-yl,pyrazolidin-3-yl), pyrazolinyl (e.g., pyrazolin-1-yl),tetrahydropyrimidinyl (e.g., tetrahydropyrimidin-1-yl), dihydrotriazolyl(e.g., 2,3-dihydro-1H-1,2,3-triazol-1-yl), tetrahydrotriazolyl (e.g.,2,3,4,5-tetrahydro-1H-1,2,3-triazol-1-yl), azepanyl (e.g., 1-azepanyl,2-azepanyl, 3-azepanyl, 4-azepanyl), dihydropyridyl (e.g.,dihydropyridin-1-yl, dihydropyridin-2-yl, dihydropyridin-3-yl,dihydropyridin-4-yl), tetrahydropyridyl (e.g.,1,2,3,4-tetrahydropyridin-1-yl, 1,2,3,4-tetrahydropyridin-2-yl,1,2,3,4-tetrahydropyridin-3-yl, 1,2,3,4-tetrahydropyridin-4-yl) and thelike.

In the present specification, examples of the “fused non-aromaticheterocyclic group” include a 8- to 12-membered fused non-aromaticheterocyclic group, specifically, a group derived from a fused ringwherein a ring corresponding to the 3- to 8-membered monocyclicnon-aromatic heterocyclic group is fused with a C₆₋₁₄ aromatichydrocarbon; a group derived from a fused ring wherein ringscorresponding to the 3- to 8-membered monocyclic non-aromaticheterocyclic groups are fused; a group derived from a fused ring whereina ring corresponding to the 3- to 8-membered monocyclic non-aromaticheterocyclic group is fused with a ring corresponding to the 5- to7-membered monocyclic aromatic heterocyclic group; and a group whereinthe above-mentioned group is partially saturated. Examples thereofinclude dihydroindolyl (e.g., 2,3-dihydro-1H-indol-1-yl),dihydroisoindolyl (e.g., 1,3-dihydro-2H-isoindol-2-yl),dihydrobenzofuranyl (e.g., 2,3-dihydro-1-benzofuran-5-yl),tetrahydrobenzofuranyl (e.g., 4,5,6,7-tetrahydro-1-benzofuran-3-yl),dihydrobenzodioxinyl (e.g., 2,3-dihydro-1,4-benzodioxin-2-yl),dihydrobenzodioxepinyl (e.g., 3,4-dihydro-2H-1,5-benzodioxepin-2-yl),chromenyl (e.g., 4H-chromen-2-yl, 2H-chromen-3-yl), dihydrochromenyl(e.g., 3,4-dihydro-2H-chromen-2-yl), dihydroquinolyl (e.g.,1,2-dihydroquinolin-4-yl), tetrahydroquinolyl (e.g.,1,2,3,4-tetrahydroquinolin-4-yl), dihydroisoquinolyl (e.g.,1,2-dihydroisoquinolin-4-yl), tetrahydroisoquinolyl (e.g.,1,2,3,4-tetrahydroisoquinolin-4-yl), dihydrophthalazinyl (e.g.,1,4-dihydrophthalazin-4-yl) and the like.

In the present specification, examples of the “5- or 6-membered aromaticheterocyclic group” include furyl (e.g., 2-furyl, 3-furyl), thienyl(e.g., 2-thienyl, 3-thienyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl,4-pyridyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl,5-pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl),pyrazinyl (e.g., 2-pyrazinyl), pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl,3-pyrrolyl), imidazolyl (e.g., 1-imidazolyl, 2-imidazolyl, 4-imidazolyl,5-imidazolyl), pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl),thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), isothiazolyl(e.g., 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), oxazolyl (e.g.,2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (e.g., 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (e.g., 1,2,4-oxadiazol-5-yl,1,3,4-oxadiazol-2-yl), thiadiazolyl (e.g., 1,3,4-thiadiazol-2-yl),triazolyl (e.g., 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl,1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl), tetrazolyl(e.g., tetrazol-1-yl, tetrazol-5-yl), triazinyl (e.g.,1,2,4-triazin-1-yl, 1,2,4-triazin-3-yl) and the like.

In the present specification, examples of the “5- or 6-memberednitrogen-containing aromatic heterocyclic group” include a 5- or6-membered nitrogen-containing aromatic heterocyclic group containing,as a ring-constituting atom besides carbon atoms, at least one nitrogenatom, and optionally containing 1 or 2 hetero atoms selected from anoxygen atom, a sulfur atom and a nitrogen atom. Examples thereof includepyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (e.g.,2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (e.g.,3-pyridazinyl, 4-pyridazinyl), pyrazinyl (e.g., 2-pyrazinyl), pyrrolyl(e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (e.g.,1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), pyrazolyl(e.g., 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), thiazolyl (e.g.,2-thiazolyl, 4-thiazolyl, 5-thiazolyl), isothiazolyl (e.g.,3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), oxazolyl (e.g.,2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (e.g., 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (e.g., 1,2,4-oxadiazol-5-yl,1,3,4-oxadiazol-2-yl), thiadiazolyl (e.g., 1,3,4-thiadiazol-2-yl),triazolyl (e.g., 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl,1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl), tetrazolyl(e.g., tetrazol-1-yl, tetrazol-5-yl), triazinyl (e.g.,1,2,4-triazin-1-yl, 1,2,4-triazin-3-yl) and the like.

In the present specification, the “C₆₋₁₄ aromatic hydrocarbon” means,for example, benzene, naphthalene or the like.

In the present specification, the “5- or 6-membered aromatic ring”means, for example, benzene, a 5- or 6-membered aromatic heterocycle orthe like.

In the present specification, examples of the “5- or 6-membered aromaticheterocycle” include a 5- or 6-membered monocyclic aromatic heterocyclecontaining, as a ring-constituting atom besides carbon atoms, 1 to 4hetero atoms selected from an oxygen atom, a sulfur atom (optionallyoxidized) and a nitrogen atom (optionally oxidized). Examples thereofinclude furan, thiophene, pyridine, pyrimidine, pyridazine, pyrazine,pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole,oxadiazole, thiadiazole, triazole, tetrazole, triazine and the like.

In the present specification, examples of the “5- or 6-memberednitrogen-containing aromatic heterocycle” include a 5- or 6-memberednitrogen-containing aromatic heterocycle containing, as aring-constituting atom besides carbon atoms, at least one nitrogen atom,and optionally containing 1 or 2 hetero atoms selected from an oxygenatom, a sulfur atom and a nitrogen atom. Examples thereof includepyridine, pyrimidine, pyridazine, pyrazine, pyrrole, imidazole,pyrazole, thiazole, isothiazole, oxazole, isoxazole, oxadiazole,thiadiazole, triazole, tetrazole, triazine and the like.

Each symbol of the formula (I) is explained below.

In the formula (I), R¹ is an optionally substituted C₁₋₆ alkyl group.

In the formula (I), R² is a hydrogen atom or an optionally substitutedC₁₋₆ alkyl group.

The “C₁₋₆ alkyl group” of “optionally substituted C₁₋₆ alkyl group” forR¹ or R² optionally has 1 to 5 (preferably 1 to 3) substituents atsubstitutable positions. Examples of the substituent includesubstituents selected from the following Substituent Group A. When thenumber of substituents is two or more, the substituents may be the sameor different.

Substituent Group A:

(1) a halogen atom;

(2) a cyano group;

(3) a nitro group;

(4) a hydroxy group;

(5) a C₃₋₈ cycloalkyl group optionally substituted by 1 to 3substituents selected from

-   -   (a) a halogen atom,    -   (b) a cyano group    -   (c) a C₁₋₆ alkyl group optionally substituted by 1 to 3 halogen        atoms, and    -   (d) a C₁₋₆ alkoxy group optionally substituted by 1 to 3 halogen        atoms;        (6) a C₆₋₁₄ aryl group optionally substituted by 1 to 3        substituents selected from    -   (a) a halogen atom,    -   (b) a cyano group,    -   (c) a C₁₋₆ alkyl group optionally substituted by 1 to 3 halogen        atoms, and    -   (d) a C₁₋₆ alkoxy group optionally substituted by 1 to 3 halogen        atoms;        (7) a C₁₋₆ alkoxy group optionally substituted by 1 to 3        substituents selected from    -   (a) a halogen atom,    -   (b) a cyano group,    -   (c) a C₃₋₈ cycloalkyl group optionally having 1 to 3 halogen        atoms,    -   (d) a C₃₋₈ cycloalkenyl group optionally having 1 to 3 halogen        atoms,    -   (e) a C₆₋₁₄ aryl group optionally having 1 to 3 halogen atoms,        and    -   (f) a 5- or 6-membered monocyclic aromatic heterocyclic group;        (8) a C₂₋₆ alkenyloxy group (e.g., vinyloxy, propenyloxy,        butenyloxy, pentenyloxy, hexenyloxy) optionally having 1 to 3        halogen atoms;        (9) a C₂₋₆ alkynyloxy group (e.g., ethynyloxy, propynyloxy,        butynyloxy, pentynyloxy, hexynyloxy) optionally having 1 to 3        halogen atoms;        (10) a C₃₋₈ cycloalkyloxy group (e.g., cyclopropyloxy,        cyclobutyloxy, cyclopentyloxy, cyclohexyloxy) optionally having        1 to 3 halogen atoms;        (11) a C₃₋₈ cycloalkenyloxy group (e.g., cyclopropenyloxy,        cyclobutenyloxy, cyclopentenyloxy, cyclohexenyloxy) optionally        having 1 to 3 halogen atoms;        (12) a C₆₋₁₄ aryloxy group optionally having 1 to 3 halogen        atoms;        (13) a C₇₋₁₄ aralkyloxy group optionally having 1 to 3 halogen        atoms;        (14) a carbamoyl group optionally mono- or di-substituted by        substituent(s) selected from    -   (a) a C₁₋₆ alkyl group,    -   (b) a C₃₋₆ cycloalkyl group,    -   (c) a C₆₋₁₄ aryl group,    -   (d) a C₁₋₆ alkoxy group,    -   (e) a 5- or 6-membered monocyclic aromatic heterocyclic group,    -   (f) a 8- to 12-membered fused aromatic heterocyclic group,    -   (g) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group, and    -   (h) a 8- to 12-membered fused non-aromatic heterocyclic group;        (15) a sulfamoyl group optionally mono- or di-substituted by        substituent(s) selected from    -   (a) a C₁₋₆ alkyl group,    -   (b) a C₃₋₆ cycloalkyl group,    -   (c) a C₆₋₁₄ aryl group,    -   (d) a C₁₋₆ alkoxy group,    -   (e) a 5- or 6-membered monocyclic aromatic heterocyclic group,    -   (f) a 8- to 12-membered fused aromatic heterocyclic group,    -   (g) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group, and    -   (h) a 8- to 12-membered fused non-aromatic heterocyclic group;        (16) a formyl group;        (17) a C₁₋₆ alkyl-carbonyl group;        (18) a C₂₋₆ alkenyl-carbonyl group (e.g., acryloyl, butenoyl,        pentenoyl, hexenoyl, heptenoyl);        (19) a C₂₋₆ alkynyl-carbonyl group (e.g., propioloyl,        propynylcarbonyl, butynylcarbonyl, pentynylcarbonyl,        hexynylcarbonyl);        (20) a C₃₋₈ cycloalkyl-carbonyl group (e.g.,        cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl,        cyclohexylcarbonyl);        (21) a C₃₋₈ cycloalkenyl-carbonyl group (e.g.,        cyclopropenylcarbonyl, cyclobutenylcarbonyl,        cyclopentenylcarbonyl, cyclohexenylcarbonyl);        (22) a C₆₋₁₄ aryl-carbonyl group (e.g., benzoyl,        1-naphthylcarbonyl, 2-naphthylcarbonyl);        (23) a C₃₋₈ cycloalkyl-C₁₋₆ alkyl-carbonyl group (e.g.,        cyclopropylacetyl, 3-cyclopropylpropionyl, cyclobutylacetyl,        cyclopentylacetyl, cyclohexylacetyl, cyclohexylpropionyl);        (24) a C₃₋₈ cycloalkenyl-C₁₋₆ alkyl-carbonyl group (e.g.,        cyclopentenylacetyl, cyclohexenylacetyl,        3-cyclohexenylpropionyl, 3-cyclohexenylpropionyl);        (25) a C₇₋₁₄ aralkyl-carbonyl group (e.g., phenylacetyl,        3-phenylpropionyl);        (26) a 5- or 6-membered monocyclic aromatic heterocyclylcarbonyl        group (e.g., furylcarbonyl, thienylcarbonyl, pyrrolylcarbonyl,        oxazolylcarbonyl, isooxazolylcarbonyl, thiazolylcarbonyl,        isothiazolylcarbonyl, imidazolylcarbonyl, pyridylcarbonyl,        pyrazolylcarbonyl);        (27) a 8- to 12-membered fused aromatic heterocyclylcarbonyl        group (e.g., benzofuranylcarbonyl, isobenzofuranylcarbonyl,        benzothienylcarbonyl, isobenzothienylcarbonyl, indolylcarbonyl,        isoindolylcarbonyl, indazolylcarbonyl, benzimidazolylcarbonyl,        benzoxazolylcarbonyl);        (28) a 3- to 8-membered monocyclic non-aromatic        heterocyclylcarbonyl group (e.g., oxiranylcarbonyl,        azetidinylcarbonyl, oxetanylcarbonyl, thietanylcarbonyl,        pyrrolidinylcarbonyl, tetrahydrofurylcarbonyl,        thioranylcarbonyl, piperidylcarbonyl);        (29) a 8- to 12-membered fused non-aromatic heterocyclylcarbonyl        group (e.g., dihydrobenzofuranyl);        (30) an amino group optionally mono- or di-substituted by        substituent(s) selected from    -   (a) a C₁₋₆ alkyl group optionally having 1 to 3 halogen atoms,    -   (b) a C₁₋₆ alkyl-carbonyl group optionally having 1 to 3 halogen        atoms,    -   (c) a C₃₋₈ cycloalkyl-carbonyl group,    -   (d) a C₆₋₁₄ aryl-carbonyl group optionally having 1 to 3 halogen        atoms,    -   (e) a 5- or 6-membered monocyclic aromatic heterocyclylcarbonyl        group,    -   (f) a 8- to 12-membered fused aromatic heterocyclylcarbonyl        group,    -   (g) a 3- to 8-membered monocyclic non-aromatic        heterocyclylcarbonyl group, and    -   (h) a 8- to 12-membered fused non-aromatic heterocyclylcarbonyl        group;        (31) a sulfanyl group;        (32) a C₁₋₆ alkylsulfanyl group (e.g., methylsulfanyl,        ethylsulfanyl);        (33) a C₂₋₆ alkenylsulfanyl group (e.g., vinylsulfanyl,        propenylsulfanyl);        (34) a C₂₋₆ alkynylsulfanyl group (e.g., ethynylsulfanyl,        propynylsulfanyl);        (35) a C₃₋₈ cycloalkylsulfanyl group (e.g., cyclopropylsulfanyl,        cyclobutylsulfanyl);        (36) a C₃₋₈ cycloalkenylsulfanyl group (e.g.,        cyclopropenylsulfanyl, cyclobutenylsulfanyl);        (37) a C₆₋₁₄ arylsulfanyl group (e.g., phenylsulfanyl);        (38) a C₃₋₈ cycloalkyl-C₁₋₆ alkylsulfanyl group (e.g.,        cyclopropylmethylsulfanyl);        (39) a C₃₋₈ cycloalkenyl-C₁₋₆ alkylsulfanyl group (e.g.,        cyclopentenylmethylsulfanyl);        (40) a C₁₋₆ alkylsulfinyl group (e.g., methylsulfinyl,        ethylsulfinyl);        (41) a C₂₋₆ alkenylsulfinyl group (e.g., vinylsulfinyl,        propenylsulfinyl);        (42) a C₂₋₆ alkynylsulfinyl group (e.g., ethynylsulfinyl,        propynylsulfinyl);        (43) a C₃₋₈ cycloalkylsulfinyl group (e.g., cyclopropylsulfinyl,        cyclobutylsulfinyl);        (44) a C₃₋₈ cycloalkenylsulfinyl group (e.g.,        cyclopropenylsulfinyl, cyclobutenylsulfinyl);        (45) a C₆₋₁₄ arylsulfinyl group (e.g., phenylsulfinyl);        (46) a C₃₋₈ cycloalkyl-C₁₋₆ alkylsulfinyl group (e.g.,        cyclopropylmethylsulfinyl);        (47) a C₃₋₈ cycloalkenyl-C₁₋₆ alkylsulfinyl group (e.g.,        cyclopentenylmethylsulfinyl);        (48) a C₁₋₆ alkylsulfonyl group (e.g., methylsulfonyl,        ethylsulfonyl);        (49) a C₂₋₆ alkenylsulfonyl group (e.g., vinylsulfonyl,        propenylsulfonyl);        (50) a C₂₋₆ alkynylsulfonyl group (e.g., ethynylsulfonyl,        propynylsulfonyl);        (51) a C₃₋₈ cycloalkylsulfonyl group (e.g., cyclopropylsulfonyl,        cyclobutylsulfonyl);        (52) a C₃₋₈ cycloalkenylsulfonyl group (e.g.,        cyclopropenylsulfonyl, cyclobutenylsulfonyl);        (53) a C₆₋₁₄ arylsulfonyl group (e.g., phenylsulfonyl);        (54) a C₃₋₈ cycloalkyl-C₁₋₆ alkylsulfonyl group (e.g.,        cyclopropylmethylsulfonyl);        (55) a C₃₋₈ cycloalkenyl-C₁₋₆ alkylsulfonyl group (e.g.,        cyclopentenylmethylsulfonyl);        (56) a C₆₋₁₄ aryl-C₁₋₆ alkylsulfonyl group (e.g.,        benzylsulfonyl);        (57) a 5- or 6-membered monocyclic aromatic heterocyclylsulfonyl        group (e.g., furylsulfonyl, thienylsulfonyl, pyridylsulfonyl);        (58) a 8- to 12-membered fused aromatic heterocyclylsulfonyl        group (e.g., benzofuranylsulfonyl, isobenzofuranylsulfonyl);        (59) a 3- to 8-membered monocyclic non-aromatic        heterocyclylsulfonyl group (e.g., oxiranylsulfonyl,        azetidinylsulfonyl);        (60) a 8- to 12-membered fused non-aromatic heterocyclylsulfonyl        group (e.g., dihydrobenzofuranylsulfonyl);        (61) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl,        thiazolyl, isothiazolyl, imidazolyl, pyridyl, pyrazolyl,        morpholinyl) optionally substituted by 1 to 3 substituents        selected from    -   (a) a halogen atom,    -   (b) a C₁₋₆ alkyl group optionally substituted by 1 to 3 halogen        atoms, and    -   (c) a C₁₋₆ alkoxy group optionally substituted by 1 to 3 halogen        atoms;        (62) a 8- to 12-membered fused aromatic heterocyclic group        (e.g., benzofuranyl, isobenzofuranyl, benzothienyl,        isobenzothienyl, indolyl, isoindolyl, indazolyl, benzimidazolyl,        benzoxazolyl) optionally substituted by 1 to 3 substituents        selected from    -   (a) a halogen atom,    -   (b) a C₁₋₆ alkyl group optionally substituted by 1 to 3 halogen        atoms, and    -   (c) a C₁₋₆ alkoxy group optionally substituted by 1 to 3 halogen        atoms;        (63) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., oxiranyl, azetidinyl, oxetanyl, thietanyl,        pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl,        piperazinyl, dihydrooxadiazolyl, thiazolinyl) optionally        substituted by 1 to 3 substituents selected from    -   (a) a halogen atom,    -   (b) a C₁₋₆ alkyl group optionally substituted by 1 to 3 halogen        atoms,    -   (c) a C₁₋₆ alkoxy group optionally substituted by 1 to 3 halogen        atoms, and    -   (d) an oxo group;        (64) a 8- to 12-membered fused non-aromatic heterocyclic group        (e.g., dihydrobenzofuranyl) optionally substituted by 1 to 3        substituents selected from    -   (a) a halogen atom,    -   (b) a C₁₋₆ alkyl group optionally substituted by 1 to 3 halogen        atoms,    -   (c) a C₁₋₆ alkoxy group optionally substituted by 1 to 3 halogen        atoms, and    -   (d) an oxo group;        (65) a 5- or 6-membered monocyclic aromatic heterocyclyloxy        group (e.g., furyloxy, thienyloxy, pyrrolyloxy, oxazolyloxy,        isooxazolyloxy, thiazolyloxy, isothiazolyloxy, imidazolyloxy,        pyridyloxy, pyrazolyloxy);        (66) a 8- to 12-membered fused aromatic heterocyclyloxy group        (e.g., benzofuranyloxy, isobenzofuranyloxy, benzothienyloxy,        isobenzothienyloxy, indolyloxy, isoindolyloxy, indazolyloxy,        benzimidazolyloxy, benzoxazolyloxy);        (67) a 3- to 8-membered monocyclic non-aromatic heterocyclyloxy        group (e.g., oxiranyloxy, azetidinyloxy, oxetanyloxy,        thietanyloxy, pyrrolidinyloxy, tetrahydrofuryloxy, thioranyloxy,        piperidyloxy);        (68) a 8- to 12-membered fused non-aromatic heterocyclyloxy        group (e.g., dihydrobenzofuranyloxy);        (69) a carboxy group;        (70) a C₁₋₆ alkoxy-carbonyl group;        (71) a C₂₋₆ alkenyloxy-carbonyl group (e.g., vinyloxycarbonyl,        propenyloxycarbonyl, butenyloxycarbonyl, pentenyloxycarbonyl,        hexenyloxycarbonyl);        (72) a C₂₋₆ alkynyloxy-carbonyl group (e.g., ethynyloxycarbonyl,        propynyloxycarbonyl, butynyloxycarbonyl, pentynyloxycarbonyl,        hexynyloxycarbonyl);        (73) a C₃₋₈ cycloalkyloxy-carbonyl group (e.g.,        cyclopropyloxycarbonyl, cyclobutyloxycarbonyl,        cyclopentyloxycarbonyl, cyclohexyloxycarbonyl);        (74) a C₃₋₈ cycloalkenyloxy-carbonyl group (e.g.,        cyclopropenyloxycarbonyl, cyclobutenyloxycarbonyl,        cyclopentenyloxycarbonyl, cyclohexenyloxycarbonyl);        (75) a C₆₋₁₄ aryloxy-carbonyl group (e.g., phenoxycarbonyl,        1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl);        (76) a C₃₋₈ cycloalkyl-C₁₋₆ alkoxy-carbonyl group (e.g.,        cyclopropylmethyloxycarbonyl, cyclopropylethyloxycarbonyl,        cyclobutylmethyloxycarbonyl, cyclopentylmethyloxycarbonyl,        cyclohexylmethyloxycarbonyl, cyclohexylethyloxycarbonyl);        (77) a C₃₋₈ cycloalkenyl-C₁₋₆ alkoxy-carbonyl group (e.g.,        cyclopentenylmethyloxycarbonyl, cyclohexenylmethyloxycarbonyl,        cyclohexenylethyloxycarbonyl, cyclohexenylpropyloxycarbonyl);        (78) a C₇₋₁₄ aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl,        phenethyloxycarbonyl);        (79) a mono-C₁₋₆ alkylthiocarbamoyl group (e.g.,        methylthiocarbamoyl, ethylthiocarbamoyl, propylthiocarbamoyl);        (80) a di-C_(1G) alkylthiocarbamoyl group (e.g.,        dimethylthiocarbamoyl, diethylthiocarbamoyl,        dipropylthiocarbamoyl);        (81) a C₁₋₆ alkyl-carbonyloxy group (e.g., acetyloxy,        propanoyloxy, butanoyloxy, 2-methylpropanoyloxy);        (82) an imino group optionally substituted by a hydroxy group;        and        (83) a C₁₋₆ alkylenedioxy group (e.g., methylenedioxy,        ethylenedioxy).

In one preferable embodiment, R¹ is preferably a C₁₋₆ alkyl group(preferably a C₁₋₃ alkyl group (e.g., methyl, ethyl, propyl, isopropyl))optionally substituted by 1 to 3 substituents selected from

-   -   (1) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by        1 to 3 substituents selected from        -   (a) a halogen atom (e.g., a fluorine atom),        -   (b) a cyano group, and        -   (c) a C₁₋₆ alkoxy group (e.g., methoxy) optionally            substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),    -   (2) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., pyridyl), and    -   (3) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., thiazolinyl).

In another preferable embodiment, R¹ is preferably a C₁₋₆ alkyl group(preferably a C₁₋₃ alkyl group (e.g., methyl, ethyl, propyl, isopropyl))optionally substituted by 1 to 3 substituents selected from

-   -   (1) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by        1 to 3 substituents selected from        -   (a) a halogen atom (e.g., a fluorine atom),        -   (b) a cyano group, and        -   (c) a C₁₋₆ alkoxy group (e.g., methoxy) optionally            substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),    -   (2) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., pyridyl) optionally substituted by 1 to 3 substituents        selected from        -   (a) a halogen atom (e.g., a fluorine atom),        -   (b) a cyano group, and        -   (c) a C₁₋₆ alkoxy group (e.g., methoxy) optionally            substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),            and    -   (3) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., thiazolinyl) optionally substituted by 1 to 3        substituents selected from        -   (a) a halogen atom (e.g., a fluorine atom),        -   (b) a cyano group, and        -   (c) a C₁₋₆ alkoxy group (e.g., methoxy) optionally            substituted by 1 to 3 halogen atoms (e.g., a fluorine atom).

R¹ is more preferably a C₁₋₆ alkyl group (preferably a C₁₋₃ alkyl group(e.g., methyl, ethyl, propyl, isopropyl)) optionally substituted by 1 to3 substituents selected from

-   -   (1) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by        1 to 3 substituents selected from        -   (a) a halogen atom (e.g., a fluorine atom),        -   (b) a cyano group, and        -   (c) a C₁₋₆ alkoxy group (e.g., methoxy) optionally            substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),    -   (2) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., pyridyl), and    -   (3) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., thiazolinyl).

R² is preferably a hydrogen atom or a C₁₋₆ alkyl group (preferably aC₁₋₃ alkyl group (e.g., methyl)), particularly preferably a hydrogenatom.

In the formula (I), R³ is an optionally substituted 5- or 6-memberedaromatic heterocyclic group.

The “5- or 6-membered aromatic heterocyclic group” of the “optionallysubstituted 5- or 6-membered aromatic heterocyclic group” for R³ ispreferably a 5- or 6-membered nitrogen-containing aromatic heterocyclicgroup (preferably pyridyl, pyrimidinyl, pyridazinyl or oxazolyl), morepreferably a group represented by

whereinring C¹ is an optionally substituted 6-membered nitrogen-containingaromatic heterocycle containing at least one nitrogen atom; andring C² is an optionally substituted 5-membered nitrogen-containingaromatic heterocycle containing at least one nitrogen atom,(preferably pyridyl, pyrimidinyl, pyridazinyl or oxazolyl).

The “5- or 6-membered aromatic heterocyclic group” of the “optionallysubstituted 5- or 6-membered aromatic heterocyclic group” for R³optionally has 1 to 5 (preferably 1 to 3) substituents at substitutablepositions. Examples of the substituent include substituents selectedfrom the following Substituent Group B. When the number of substituentsis two or more, the substituents may be the same or different.

Substituent Group B:

(1) the above-mentioned Substituent Group A;

(2) a C₁₋₆ alkyl group optionally substituted by 1 to 3 substituentsselected from

-   -   (a) a halogen atom,    -   (b) a cyano group,    -   (c) a hydroxy group,    -   (d) a C₃₋₈ cycloalkyl group optionally substituted by 1 to 3        substituents selected from        -   (i) a halogen atom,        -   (ii) a cyano group, and        -   (iii) a C₁₋₆ alkyl group optionally substituted by 1 to 3            halogen atoms;    -   (e) a C₆₋₁₄ aryl group optionally substituted by 1 to 3        substituents selected from        -   (i) a halogen atom,        -   (ii) a cyano group, and        -   (iii) a C₁₋₆ alkyl group optionally substituted by 1 to 3            halogen atoms,    -   (f) a C₁₋₆ alkoxy group optionally substituted by 1 to 3 halogen        atoms,    -   (g) an amino group optionally mono- or di-substituted by C₁₋₆        alkyl group(s),    -   (h) a 5- or 6-membered monocyclic aromatic heterocyclic group,    -   (i) a 8- to 12-membered fused aromatic heterocyclic group,    -   (j) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group,    -   (k) a 8- to 12-membered fused non-aromatic heterocyclic group,    -   (l) a carboxy group, and    -   (m) a C₁₋₆ alkoxy-carbonyl group optionally substituted by 1 to        3 halogen atoms;        (3) a C₂₋₆ alkenyl group optionally substituted by 1 to 3        substituents selected from    -   (a) a halogen atom,    -   (b) a hydroxy group,    -   (c) a C₁₋₆ alkoxy group,    -   (d) an amino group optionally mono- or di-substituted by C₁₋₆        alkyl group(s),    -   (e) a carboxy group, and    -   (f) a C₁₋₆ alkoxy-carbonyl group;        (4) a C₇₋₁₄ aralkyl group optionally substituted by 1 to 3        substituents selected from    -   (a) a halogen atom,    -   (b) a hydroxy group,    -   (c) a C₁₋₆ alkoxy group, and    -   (d) a C₁₋₆ alkyl group optionally substituted by 1 to 3 halogen        atoms; and        (5) an oxo group.

In one preferable embodiment, R³ is preferably a 5- or 6-memberedaromatic heterocyclic group (preferably pyridyl, pyrimidinyl,pyridazinyl or oxazolyl) optionally substituted by 1 to 3 halogen atoms(e.g., a fluorine atom).

In another preferable embodiment, R³ is preferably an optionallysubstituted 5- or 6-membered nitrogen-containing aromatic heterocyclicgroup (preferably pyridyl, pyrimidinyl, pyridazinyl or oxazolyl).

R³ is more preferably a 5- or 6-membered nitrogen-containing aromaticheterocyclic group (preferably pyridyl, pyrimidinyl, pyridazinyl oroxazolyl) optionally substituted by 1 to 3 halogen atoms (e.g., afluorine atom).

R³ is particularly preferably a group represented by

whereinring C¹ is an optionally substituted 6-membered nitrogen-containingaromatic heterocycle containing at least one nitrogen atom; andring C² is an optionally substituted 5-membered nitrogen-containingaromatic heterocycle containing at least one nitrogen atom,(preferably pyridyl, pyrimidinyl, pyridazinyl or oxazolyl), each ofwhich is optionally substituted by 1 to 3 halogen atoms (e.g., afluorine atom).

In the formula (I), ring A is a further optionally substitutedpiperidine ring (the piperidine ring is optionally bridged).

The “piperidine ring” of the “further optionally substituted piperidinering” for ring A is optionally bridged. Examples of the bridgedpiperidine ring include oxa-9-azabicyclo[3.3.1]nonane and the like.

The “piperidine ring” of the “further optionally substituted piperidinering” for ring A optionally has, besides R¹, R²—O— and —C(═O)-ring B, 1to 4 (preferably 1 to 3) substituents at substitutable positions.Examples of the substituent include substituents selected from theabove-mentioned Substituent Group B. When the number of substituents istwo or more, the substituents may be the same or different.

Ring A is preferably a piperidine ring having no substituent other thanR¹, R²—O— and —C(═O)-ring B, or an oxa-9-azabicyclo[3.3.1]nonane ringhaving no substituent other than R¹, R²—O— and —C(═O)-ring B.

Ring A is more preferably a piperidine ring having no substituent otherthan R¹, R²—O— and —C(═O)-ring B.

In the formula (I), ring B is a further optionally substituted 5- or6-membered aromatic ring (X and Y are independently a carbon atom or anitrogen atom).

In one preferable embodiment, the “5- or 6-membered aromatic ring” ofthe “further optionally substituted 5- or 6-membered aromatic ring” forring B is preferably benzene, thiazole, isoxazole, pyrazole, pyridine orpyrazine (X and Y are independently a carbon atom or a nitrogen atom),more preferably

In another preferable embodiment, the “5- or 6-membered aromatic ring”of the “further optionally substituted 5- or 6-membered aromatic ring”for ring B is preferably a 6-membered aromatic ring (X and Y areindependently a carbon atom or a nitrogen atom), more preferablybenzene, pyridine or pyrazine.

The “5- or 6-membered aromatic ring” of the “further optionallysubstituted 5- or 6-membered aromatic ring” for ring B optionally has,besides R³ and —C(═O)— ring A, 1 to 4 (preferably 1 to 3) substituentsat substitutable positions. Examples of the substituent includesubstituents selected from the above-mentioned Substituent Group B. Whenthe number of substituents is two or more, the substituents may be thesame or different.

In one preferable embodiment, ring B is preferably a 5- or 6-memberedaromatic ring (preferably benzene, thiazole, isoxazole, pyrazole,pyridine or pyrazine) (X and Y are independently a carbon atom or anitrogen atom), which is, in addition to R³ and —C(═O)— ring A,optionally substituted by 1 to 3 substituents selected from

-   -   (1) a halogen atom (e.g., a fluorine atom, a chlorine atom),    -   (2) a C₁₋₆ alkyl group (e.g., methyl, tert-butyl) optionally        substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),    -   (3) a C₁₋₆ alkoxy group (e.g., methoxy), and    -   (4) a C₁₋₆ alkylenedioxy group (e.g., methylenedioxy),        more preferably benzene, thiazole, isoxazole, pyrazole, pyridine        or pyrazine (X and Y are independently a carbon atom or a        nitrogen atom), each of which is, in addition to R³ and —C(═O)—        ring A, optionally substituted by 1 to 3 substituents selected        from    -   (1) a halogen atom (e.g., a fluorine atom, a chlorine atom),    -   (2) a C₁₋₆ alkyl group (e.g., methyl, tert-butyl) optionally        substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),    -   (3) a C₁₋₆ alkoxy group (e.g., methoxy), and    -   (4) a C₁₋₆ alkylenedioxy group (e.g., methylenedioxy),        particularly preferably

each of which is, in addition to R³ and —C(═O)— ring A, optionallysubstituted by 1 to 3 substituents selected from

-   -   (1) a halogen atom (e.g., a fluorine atom, a chlorine atom),    -   (2) a C₁₋₆ alkyl group (e.g., methyl, tert-butyl) optionally        substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),    -   (3) a C₁₋₆ alkoxy group (e.g., methoxy), and    -   (4) a C₁₋₆ alkylenedioxy group (e.g., methylenedioxy).

In another preferable embodiment, ring B is preferably a 6-memberedaromatic ring (X and Y are independently a carbon atom or a nitrogenatom, preferably benzene, pyridine or pyrazine), which is, in additionto R³ and —C(═O)— ring A, optionally substituted by 1 to 3 substituentsselected from

-   -   (1) a halogen atom (e.g., a fluorine atom, a chlorine atom),    -   (2) a C₁₋₆ alkyl group (e.g., methyl, tert-butyl) optionally        substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),    -   (3) a C₁₋₆ alkoxy group (e.g., methoxy), and    -   (4) a C₁₋₆ alkylenedioxy group (e.g., methylenedioxy).

Preferable examples of compound (I) include the following compounds.

[Compound A]

Compound (I) wherein

R¹ is a C₁₋₆ alkyl group (preferably a C₁₋₃ alkyl group (e.g., methyl,ethyl, propyl, isopropyl)) optionally substituted by 1 to 3 substituentsselected from

-   -   (1) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by        1 to 3 substituents selected from        -   (a) a halogen atom (e.g., a fluorine atom),        -   (b) a cyano group, and        -   (c) a C₁₋₆ alkoxy group (e.g., methoxy) optionally            substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),    -   (2) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., pyridyl), and    -   (3) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., thiazolinyl);        R² is a hydrogen atom or a C₁₋₆ alkyl group (preferably a C₁₋₃        alkyl group (e.g., methyl));        R³ is a 5- or 6-membered aromatic heterocyclic group (preferably        pyridyl, pyrimidinyl, pyridazinyl or oxazolyl) optionally        substituted by 1 to 3 halogen atoms (e.g., a fluorine atom);        ring A is a piperidine ring having no substituent other than R¹,        R²—O— and —C(═O)-ring B; and        ring B is a 5- or 6-membered aromatic ring (preferably benzene,        thiazole, isoxazole, pyrazole, pyridine or pyrazine) (X and Y        are independently a carbon atom or a nitrogen atom), which is,        in addition to R³ and —C(═O)— ring A, optionally substituted by        1 to 3 substituents selected from    -   (1) a halogen atom (e.g., a fluorine atom, a chlorine atom),    -   (2) a C₁₋₆ alkyl group (e.g., methyl, tert-butyl) optionally        substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),    -   (3) a C₁₋₆ alkoxy group (e.g., methoxy), and    -   (4) a C₁₋₆ alkylenedioxy group (e.g., methylenedioxy),        or a salt thereof.        [Compound B1]

Compound (I) wherein

R¹ is a C₁₋₆ alkyl group (preferably a C₁₋₃ alkyl group (e.g., methyl,ethyl, propyl, isopropyl)) optionally substituted by 1 to 3 substituentsselected from

-   -   (1) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by        1 to 3 substituents selected from        -   (a) a halogen atom (e.g., a fluorine atom),        -   (b) a cyano group, and        -   (c) a C₁₋₆ alkoxy group (e.g., methoxy) optionally            substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),    -   (2) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., pyridyl), and    -   (3) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., thiazolinyl);        R² is a hydrogen atom or a C₁₋₆ alkyl group (preferably a C₁₋₃        alkyl group (e.g., methyl)) (preferably a hydrogen atom);        R³ is a 5- or 6-membered nitrogen-containing aromatic        heterocyclic group (preferably pyridyl, pyrimidinyl, pyridazinyl        or oxazolyl) optionally substituted by 1 to 3 halogen atoms        (e.g., a fluorine atom);        ring A is a piperidine ring having no substituent other than R¹,        R²—O— and —C(═O)-ring B; and        ring B is benzene, thiazole, isoxazole, pyrazole, pyridine or        pyrazine (X and Y are independently a carbon atom or a nitrogen        atom), each of which is, in addition to R³ and —C(═O)— ring A,        optionally substituted by 1 to 3 substituents selected from    -   (1) a halogen atom (e.g., a fluorine atom, a chlorine atom),    -   (2) a C₁₋₆ alkyl group (e.g., methyl, tert-butyl) optionally        substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),    -   (3) a C₁₋₆ alkoxy group (e.g., methoxy), and    -   (4) a C₁₋₆ alkylenedioxy group (e.g., methylenedioxy),        or a salt thereof.        [Compound B2]

Compound (I) wherein

R¹ is a C₁₋₆ alkyl group (preferably a C₁₋₃ alkyl group (e.g., methyl,ethyl, propyl, isopropyl)) optionally substituted by 1 to 3 substituentsselected from

-   -   (1) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by        1 to 3 substituents selected from        -   (a) a halogen atom (e.g., a fluorine atom),        -   (b) a cyano group, and        -   (c) a C₁₋₆ alkoxy group (e.g., methoxy) optionally            substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),    -   (2) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., pyridyl), and    -   (3) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., thiazolinyl);        R² is a hydrogen atom or a C₁₋₆ alkyl group (preferably a C₁₋₃        alkyl group (e.g., methyl)) (preferably a hydrogen atom);        R³ is a 5- or 6-membered nitrogen-containing aromatic        heterocyclic group (preferably pyridyl, pyrimidinyl, pyridazinyl        or oxazolyl) optionally substituted by 1 to 3 halogen atoms        (e.g., a fluorine atom);        ring A is a piperidine ring having no substituent other than R¹,        R²—O— and —C(═O)-ring B; and        ring B is a 6-membered aromatic ring (X and Y are independently        a carbon atom or a nitrogen atom, preferably benzene, pyridine        or pyrazine), which is, in addition to R³ and —C(═O)— ring A,        optionally substituted by 1 to 3 substituents selected from    -   (1) a halogen atom (e.g., a fluorine atom, a chlorine atom),    -   (2) a C₁₋₆ alkyl group (e.g., methyl, tert-butyl) optionally        substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),    -   (3) a C₁₋₆ alkoxy group (e.g., methoxy), and    -   (4) a C₁₋₆ alkylenedioxy group (e.g., methylenedioxy), or a salt        thereof.        [Compound C]

Compound (I) wherein

R¹ is a C₁₋₆ alkyl group (preferably a C₁₋₃ alkyl group (e.g., methyl,ethyl, propyl, isopropyl)) optionally substituted by 1 to 3 substituentsselected from

-   -   (1) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by        1 to 3 substituents selected from        -   (a) a halogen atom (e.g., a fluorine atom),        -   (b) a cyano group, and        -   (c) a C₁₋₆ alkoxy group (e.g., methoxy) optionally            substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),    -   (2) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., pyridyl), and    -   (3) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., thiazolinyl);        R² is a hydrogen atom or a C₁₋₆ alkyl group (preferably a C₁₋₃        alkyl group (e.g., methyl)) (preferably a hydrogen atom);        R³ is a group represented by

whereinring C¹ is an optionally substituted 6-membered nitrogen-containingaromatic heterocycle containing at least one nitrogen atom; andring C² is an optionally substituted 5-membered nitrogen-containingaromatic heterocycle containing at least one nitrogen atom,(preferably pyridyl, pyrimidinyl, pyridazinyl or oxazolyl), each ofwhich is optionally substituted by 1 to 3 halogen atoms (e.g., afluorine atom);ring A is a piperidine ring having no substituent other than R¹, R²—O—and —C(═O)-ring B; andring B is

each of which is, in addition to R³ and —C(═O)— ring A, optionallysubstituted by 1 to 3 substituents selected from

-   -   (1) a halogen atom (e.g., a fluorine atom, a chlorine atom),    -   (2) a C₁₋₆ alkyl group (e.g., methyl, tert-butyl) optionally        substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),    -   (3) a C₁₋₆ alkoxy group (e.g., methoxy), and    -   (4) a C₁₋₆ alkylenedioxy group (e.g., methylenedioxy),        or a salt thereof.        [Compound D1]

Compound (I) wherein

R¹ is a C₁₋₆ alkyl group (preferably a C₁₋₃ alkyl group (e.g., methyl,ethyl, propyl, isopropyl)) optionally substituted by 1 to 3 substituentsselected from

-   -   (1) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by        1 to 3 substituents selected from        -   (a) a halogen atom (e.g., a fluorine atom),        -   (b) a cyano group, and        -   (c) a C₁₋₆ alkoxy group (e.g., methoxy) optionally            substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),    -   (2) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., pyridyl) optionally substituted by 1 to 3 substituents        selected from        -   (a) a halogen atom (e.g., a fluorine atom),        -   (b) a cyano group, and        -   (c) a C₁₋₆ alkoxy group (e.g., methoxy) optionally            substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),            and    -   (3) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., thiazolinyl) optionally substituted by 1 to 3        substituents selected from        -   (a) a halogen atom (e.g., a fluorine atom),        -   (b) a cyano group, and        -   (c) a C₁₋₆ alkoxy group (e.g., methoxy) optionally            substituted by 1 to 3 halogen atoms (e.g., a fluorine atom);            R² is a hydrogen atom or a C₁₋₆ alkyl group (preferably a            C₁₋₃ alkyl group (e.g., methyl)) (preferably a hydrogen            atom);            R³ is a 5- or 6-membered nitrogen-containing aromatic            heterocyclic group (preferably pyridyl, pyrimidinyl,            pyridazinyl or oxazolyl) optionally substituted by 1 to 3            halogen atoms (e.g., a fluorine atom);            ring A is a piperidine ring having no substituent other than            R¹, R²—O— and —C(═O)-ring B, or an            oxa-9-azabicyclo[3.3.1]nonane ring having no substituent            other than R¹, R²—O— and —C(═O)-ring B; and            ring B is a 5- or 6-membered aromatic ring (preferably            benzene, thiazole, isoxazole, pyrazole, pyridine or            pyrazine) (X and Y are independently a carbon atom or a            nitrogen atom), which is, in addition to R³ and —C(═O)— ring            A, optionally substituted by 1 to 3 substituents selected            from    -   (1) a halogen atom (e.g., a fluorine atom, a chlorine atom),    -   (2) a C₁₋₆ alkyl group (e.g., methyl, tert-butyl) optionally        substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),    -   (3) a C₁₋₆ alkoxy group (e.g., methoxy), and    -   (4) a C₁₋₆ alkylenedioxy group (e.g., methylenedioxy), or a salt        thereof.        [Compound D2]

Compound (I) wherein

R¹ is a C₁₋₆ alkyl group (preferably a C₁₋₃ alkyl group (e.g., methyl,ethyl, propyl, isopropyl)) optionally substituted by 1 to 3 substituentsselected from

-   -   (1) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by        1 to 3 substituents selected from        -   (a) a halogen atom (e.g., a fluorine atom),        -   (b) a cyano group, and        -   (c) a C₁₋₆ alkoxy group (e.g., methoxy) optionally            substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),    -   (2) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., pyridyl), and    -   (3) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., thiazolinyl);        R² is a hydrogen atom or a C₁₋₆ alkyl group (preferably a C₁₋₃        alkyl group (e.g., methyl)) (preferably a hydrogen atom);        R³ is a 5- or 6-membered nitrogen-containing aromatic        heterocyclic group (preferably pyridyl, pyrimidinyl, pyridazinyl        or oxazolyl) optionally substituted by 1 to 3 halogen atoms        (e.g., a fluorine atom);        ring A is a piperidine ring having no substituent other than R¹,        R²—O— and —C(═O)-ring B; and        ring B is a 5- or 6-membered aromatic ring (preferably benzene,        thiazole, isoxazole, pyrazole, pyridine or pyrazine) (X and Y        are independently a carbon atom or a nitrogen atom), which is,        in addition to R³ and —C(═O)— ring A, optionally substituted by        1 to 3 substituents selected from    -   (1) a halogen atom (e.g., a fluorine atom, a chlorine atom),    -   (2) a C₁₋₆ alkyl group (e.g., methyl, tert-butyl) optionally        substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),    -   (3) a C₁₋₆ alkoxy group (e.g., methoxy) and    -   (4) a C₁₋₆ alkylenedioxy group (e.g., methylenedioxy), or a salt        thereof.        [Compound E1]

Compound (I) wherein

R¹ is a C₁₋₆ alkyl group (preferably a C₁₋₃ alkyl group (e.g., methyl,ethyl, propyl, isopropyl)) optionally substituted by 1 to 3 substituentsselected from

-   -   (1) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by        1 to 3 substituents selected from        -   (a) a halogen atom (e.g., a fluorine atom),        -   (b) a cyano group, and        -   (c) a C₁₋₆ alkoxy group (e.g., methoxy) optionally            substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),    -   (2) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., pyridyl) optionally substituted by 1 to 3 substituents        selected from        -   (a) a halogen atom (e.g., a fluorine atom),        -   (b) a cyano group, and        -   (c) a C₁₋₆ alkoxy group (e.g., methoxy) optionally            substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),            and    -   (3) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., thiazolinyl) optionally substituted by 1 to 3        substituents selected from        -   (a) a halogen atom (e.g., a fluorine atom),        -   (b) a cyano group, and        -   (c) a C₁₋₆ alkoxy group (e.g., methoxy) optionally            substituted by 1 to 3 halogen atoms (e.g., a fluorine atom);            R² is a hydrogen atom or a C₁₋₆ alkyl group (preferably a            C₁₋₃ alkyl group (e.g., methyl)) (preferably a hydrogen            atom);            R³ is a 5- or 6-membered nitrogen-containing aromatic            heterocyclic group (preferably pyridyl, pyrimidinyl,            pyridazinyl or oxazolyl) optionally substituted by 1 to 3            halogen atoms (e.g., a fluorine atom);            ring A is a piperidine ring having no substituent other than            R¹, R²—O— and —C(═O)-ring B, or an            oxa-9-azabicyclo[3.3.1]nonane ring having no substituent            other than R¹, R²—O— and —C(═O)-ring B; and            ring B is benzene, thiazole, isoxazole, pyrazole, pyridine            or pyrazine (X and Y are independently a carbon atom or a            nitrogen atom), each of which is, in addition to R³ and            —C(═O)— ring A, optionally substituted by 1 to 3            substituents selected from    -   (1) a halogen atom (e.g., a fluorine atom, a chlorine atom),    -   (2) a C₁₋₆ alkyl group (e.g., methyl, tert-butyl) optionally        substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),    -   (3) a C₁₋₆ alkoxy group (e.g., methoxy), and    -   (4) a C₁₋₆ alkylenedioxy group (e.g., methylenedioxy), or a salt        thereof.        [Compound E2]

Compound (I) wherein

R¹ is a C₁₋₆ alkyl group (preferably a C₁₋₃ alkyl group (e.g., methyl,ethyl, propyl, isopropyl)) optionally substituted by 1 to 3 substituentsselected from

-   -   (1) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by        1 to 3 substituents selected from        -   (a) a halogen atom (e.g., a fluorine atom),        -   (b) a cyano group, and        -   (c) a C₁₋₆ alkoxy group (e.g., methoxy) optionally            substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),    -   (2) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., pyridyl), and    -   (3) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., thiazolinyl);        R² is a hydrogen atom or a C₁₋₆ alkyl group (preferably a C₁₋₃        alkyl group (e.g., methyl)) (preferably a hydrogen atom);        R³ is a 5- or 6-membered nitrogen-containing aromatic        heterocyclic group (preferably pyridyl, pyrimidinyl, pyridazinyl        or oxazolyl) optionally substituted by 1 to 3 halogen atoms        (e.g., a fluorine atom);        ring A is a piperidine ring having no substituent other than R¹,        R²—O— and —C(═O)-ring B; and        ring B is benzene, thiazole, isoxazole, pyrazole, pyridine or        pyrazine (X and Y are independently a carbon atom or a nitrogen        atom), each of which is, in addition to R³ and —C(═O)— ring A,        optionally substituted by 1 to 3 substituents selected from    -   (1) a halogen atom (e.g., a fluorine atom, a chlorine atom),    -   (2) a C₁₋₆ alkyl group (e.g., methyl, tert-butyl) optionally        substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),    -   (3) a C₁₋₆ alkoxy group (e.g., methoxy), and    -   (4) a C₁₋₆ alkylenedioxy group (e.g., methylenedioxy),        or a salt thereof.        [Compound E3]

Compound (I) wherein

R¹ is a C₁₋₆ alkyl group (preferably a C₁₋₃ alkyl group (e.g., methyl,ethyl, propyl, isopropyl)) optionally substituted by 1 to 3 substituentsselected from

-   -   (1) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by        1 to 3 substituents selected from        -   (a) a halogen atom (e.g., a fluorine atom),        -   (b) a cyano group, and        -   (c) a C₁₋₆ alkoxy group (e.g., methoxy) optionally            substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),    -   (2) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., pyridyl), and    -   (3) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., thiazolinyl);        R² is a hydrogen atom or a C₁₋₆ alkyl group (preferably a C₁₋₃        alkyl group (e.g., methyl)) (preferably a hydrogen atom);        R³ is a 5- or 6-membered nitrogen-containing aromatic        heterocyclic group (preferably pyridyl, pyrimidinyl, pyridazinyl        or oxazolyl) optionally substituted by 1 to 3 halogen atoms        (e.g., a fluorine atom);        ring A is a piperidine ring having no substituent other than R¹,        R²—O— and —C(═O)-ring B; and        ring B is

each of which is, in addition to R³ and —C(═O)— ring A, optionallysubstituted by 1 to 3 substituents selected from

-   -   (1) a halogen atom (e.g., a fluorine atom, a chlorine atom),    -   (2) a C₁₋₆ alkyl group (e.g., methyl, tert-butyl) optionally        substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),    -   (3) a C₁₋₆ alkoxy group (e.g., methoxy), and    -   (4) a C₁₋₆ alkylenedioxy group (e.g., methylenedioxy), or a salt        thereof.        [Compound F1]

Compound (I) wherein

R¹ is a C₁₋₆ alkyl group (preferably a C₁₋₃ alkyl group (e.g., methyl,ethyl, propyl, isopropyl)) optionally substituted by 1 to 3 substituentsselected from

-   -   (1) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by        1 to 3 substituents selected from        -   (a) a halogen atom (e.g., a fluorine atom),        -   (b) a cyano group, and        -   (c) a C₁₋₆ alkoxy group (e.g., methoxy) optionally            substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),    -   (2) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., pyridyl) optionally substituted by 1 to 3 substituents        selected from        -   (a) a halogen atom (e.g., a fluorine atom),        -   (b) a cyano group, and        -   (c) a C₁₋₆ alkoxy group (e.g., methoxy) optionally            substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),            and    -   (3) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., thiazolinyl) optionally substituted by 1 to 3        substituents selected from        -   (a) a halogen atom (e.g., a fluorine atom),        -   (b) a cyano group, and        -   (c) a C₁₋₆ alkoxy group (e.g., methoxy) optionally            substituted by 1 to 3 halogen atoms (e.g., a fluorine atom);            R² is a hydrogen atom or a C₁₋₆ alkyl group (preferably a            C₁₋₃ alkyl group (e.g., methyl)) (preferably a hydrogen            atom);            R³ is a group represented by

whereinring C¹ is an optionally substituted 6-membered nitrogen-containingaromatic heterocycle containing at least one nitrogen atom; andring C² is an optionally substituted 5-membered nitrogen-containingaromatic heterocycle containing at least one nitrogen atom,(preferably pyridyl, pyrimidinyl, pyridazinyl or oxazolyl), each ofwhich is optionally substituted by 1 to 3 halogen atoms (e.g., afluorine atom);ring A is a piperidine ring having no substituent other than R¹, R²—O—and —C(═O)-ring B, or an oxa-9-azabicyclo[3.3.1]nonane ring having nosubstituent other than R¹, R²—O— and —C(═O)-ring B; andring B is a 5- or 6-membered aromatic ring (preferably benzene,thiazole, isoxazole, pyrazole, pyridine or pyrazine) (X and Y areindependently a carbon atom or a nitrogen atom), which is, in additionto R³ and —C(═O)— ring A, optionally substituted by 1 to 3 substituentsselected from

-   -   (1) a halogen atom (e.g., a fluorine atom, a chlorine atom),    -   (2) a C₁₋₆ alkyl group (e.g., methyl, tert-butyl) optionally        substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),    -   (3) a C₁₋₆ alkoxy group (e.g., methoxy), and    -   (4) a C₁₋₆ alkylenedioxy group (e.g., methylenedioxy),        or a salt thereof.        [Compound F2]

Compound (I) wherein

R¹ is a C₁₋₆ alkyl group (preferably a C₁₋₃ alkyl group (e.g., methyl,ethyl, propyl, isopropyl)) optionally substituted by 1 to 3 substituentsselected from

-   -   (1) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by        1 to 3 substituents selected from        -   (a) a halogen atom (e.g., a fluorine atom),        -   (b) a cyano group, and        -   (c) a C₁₋₆ alkoxy group (e.g., methoxy) optionally            substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),    -   (2) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., pyridyl), and    -   (3) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., thiazolinyl);        R² is a hydrogen atom or a C₁₋₆ alkyl group (preferably a C₁₋₃        alkyl group (e.g., methyl)) (preferably a hydrogen atom);        R³ is a group represented by

whereinring C¹ is an optionally substituted 6-membered nitrogen-containingaromatic heterocycle containing at least one nitrogen atom; andring C² is an optionally substituted 5-membered nitrogen-containingaromatic heterocycle containing at least one nitrogen atom,(preferably pyridyl, pyrimidinyl, pyridazinyl or oxazolyl), each ofwhich is optionally substituted by 1 to 3 halogen atoms (e.g., afluorine atom);ring A is a piperidine ring having no substituent other than R¹, R²—O—and —C(═O)-ring B; andring B is a 5- or 6-membered aromatic ring (preferably benzene,thiazole, isoxazole, pyrazole, pyridine or pyrazine) (X and Y areindependently a carbon atom or a nitrogen atom), which is, in additionto R³ and —C(═O)— ring A, optionally substituted by 1 to 3 substituentsselected from

-   -   (1) a halogen atom (e.g., a fluorine atom, a chlorine atom),    -   (2) a C₁₋₆ alkyl group (e.g., methyl, tert-butyl) optionally        substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),    -   (3) a C₁₋₆ alkoxy group (e.g., methoxy), and    -   (4) a C₁₋₆ alkylenedioxy group (e.g., methylenedioxy), or a salt        thereof.        [Compound G1]

Compound (I) wherein

R¹ is a C₁₋₆ alkyl group (preferably a C₁₋₃ alkyl group (e.g., methyl,ethyl, propyl, isopropyl)) optionally substituted by 1 to 3 substituentsselected from

-   -   (1) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by        1 to 3 substituents selected from        -   (a) a halogen atom (e.g., a fluorine atom),        -   (b) a cyano group, and        -   (c) a C₁₋₆ alkoxy group (e.g., methoxy) optionally            substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),    -   (2) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., pyridyl) optionally substituted by 1 to 3 substituents        selected from        -   (a) a halogen atom (e.g., a fluorine atom),        -   (b) a cyano group, and        -   (c) a C₁₋₆ alkoxy group (e.g., methoxy) optionally            substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),            and    -   (3) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., thiazolinyl) optionally substituted by 1 to 3        substituents selected from        -   (a) a halogen atom (e.g., a fluorine atom),        -   (b) a cyano group, and        -   (c) a C₁₋₆ alkoxy group (e.g., methoxy) optionally            substituted by 1 to 3 halogen atoms (e.g., a fluorine atom);            R² is a hydrogen atom or a C₁₋₆ alkyl group (preferably a            C₁₋₃ alkyl group (e.g., methyl)) (preferably a hydrogen            atom);            R³ is a group represented by

whereinring C¹ is an optionally substituted 6-membered nitrogen-containingaromatic heterocycle containing at least one nitrogen atom; andring C² is an optionally substituted 5-membered nitrogen-containingaromatic heterocycle containing at least one nitrogen atom,(preferably pyridyl, pyrimidinyl, pyridazinyl or oxazolyl), each ofwhich is optionally substituted by 1 to 3 halogen atoms (e.g., afluorine atom);ring A is a piperidine ring having no substituent other than R¹, R²—O—and —C(═O)-ring B, or an oxa-9-azabicyclo[3.3.1]nonane ring having nosubstituent other than R¹, R²—O— and —C(═O)-ring B; andring B is benzene, thiazole, isoxazole, pyrazole, pyridine or pyrazine(X and Y are independently a carbon atom or a nitrogen atom), each ofwhich is, in addition to R³ and —C(═O)— ring A, optionally substitutedby 1 to 3 substituents selected from

-   -   (1) a halogen atom (e.g., a fluorine atom, a chlorine atom),    -   (2) a C₁₋₆ alkyl group (e.g., methyl, tert-butyl) optionally        substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),    -   (3) a C₁₋₆ alkoxy group (e.g., methoxy), and    -   (4) a C₁₋₆ alkylenedioxy group (e.g., methylenedioxy),        or a salt thereof.        [Compound G2]

Compound (I) wherein

R¹ is a C₁₋₆ alkyl group (preferably a C₁₋₃ alkyl group (e.g., methyl,ethyl, propyl, isopropyl)) optionally substituted by 1 to 3 substituentsselected from

-   -   (1) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by        1 to 3 substituents selected from        -   (a) a halogen atom (e.g., a fluorine atom),        -   (b) a cyano group, and        -   (c) a C₁₋₆ alkoxy group (e.g., methoxy) optionally            substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),    -   (2) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., pyridyl), and    -   (3) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., thiazolinyl);        R² is a hydrogen atom or a C₁₋₆ alkyl group (preferably a C₁₋₃        alkyl group (e.g., methyl)) (preferably a hydrogen atom);        R³ is a group represented by

whereinring C¹ is an optionally substituted 6-membered nitrogen-containingaromatic heterocycle containing at least one nitrogen atom; andring C² is an optionally substituted 5-membered nitrogen-containingaromatic heterocycle containing at least one nitrogen atom,(preferably pyridyl, pyrimidinyl, pyridazinyl or oxazolyl), each ofwhich is optionally substituted by 1 to 3 halogen atoms (e.g., afluorine atom);ring A is a piperidine ring having no substituent other than R¹, R²—O—and —C(═O)-ring B; andring B is

each of which is, in addition to R³ and —C(═O)— ring A, optionallysubstituted by 1 to 3 substituents selected from

-   -   (1) a halogen atom (e.g., a fluorine atom, a chlorine atom),    -   (2) a C₁₋₆ alkyl group (e.g., methyl, tert-butyl) optionally        substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),    -   (3) a C₁₋₆ alkoxy group (e.g., methoxy), and    -   (4) a C₁₋₆ alkylenedioxy group (e.g., methylenedioxy),        or a salt thereof.        [Compound G3]

Compound (I) wherein

R¹ is a C₁₋₆ alkyl group (preferably a C₁₋₃ alkyl group (e.g., methyl,ethyl, propyl, isopropyl)) optionally substituted by 1 to 3 substituentsselected from

-   -   (1) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by        1 to 3 substituents selected from        -   (a) a halogen atom (e.g., a fluorine atom),        -   (b) a cyano group, and        -   (c) a C₁₋₆ alkoxy group (e.g., methoxy) optionally            substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),    -   (2) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., pyridyl), and    -   (3) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., thiazolinyl);        R² is a hydrogen atom;        R³ is a group represented by

whereinring C¹ is an optionally substituted 6-membered nitrogen-containingaromatic heterocycle containing at least one nitrogen atom; andring C² is an optionally substituted 5-membered nitrogen-containingaromatic heterocycle containing at least one nitrogen atom,(preferably pyridyl, pyrimidinyl, pyridazinyl or oxazolyl), each ofwhich is optionally substituted by 1 to 3 halogen atoms (e.g., afluorine atom);ring A is a piperidine ring having no substituent other than R¹, R²—O—and —C(═O)-ring B; andring B is

each of which is, in addition to R³ and —C(═O)— ring A, optionallysubstituted by 1 to 3 substituents selected from

-   -   (1) a halogen atom (e.g., a fluorine atom, a chlorine atom),    -   (2) a C₁₋₆ alkyl group (e.g., methyl, tert-butyl) optionally        substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),    -   (3) a C₁₋₆ alkoxy group (e.g., methoxy), and    -   (4) a C₁₋₆ alkylenedioxy group (e.g., methylenedioxy), or a salt        thereof.        [Compound G4]

Compound (I) selected from

-   (4-benzyl-4-hydroxypiperidin-1-yl) (2,4′-bipyridin-3-yl)methanone,-   2,4′-bipyridin-3-yl(4-(4-fluorobenzyl)-4-hydroxypiperidin-1-yl)methanone,-   2,4′-bipyridin-3-yl(4-(2,4-difluorobenzyl)-4-hydroxypiperidin-1-yl)methanone,    and-   (4-(4-fluorobenzyl)-4-hydroxypiperidin-1-yl)    (2-(pyrimidin-4-yl)pyridin-3-yl)methanone    or a salt thereof.

When compound (I) is in a form of a salt, examples thereof include metalsalts, an ammonium salt, salts with organic base, salts with inorganicacid, salts with organic acid, salts with basic or acidic amino acid,and the like. Preferable examples of the metal salt include alkali metalsalts such as sodium salt, potassium salt and the like; alkaline earthmetal salts such as calcium salt, magnesium salt, barium salt and thelike; an aluminum salt, and the like. Preferable examples of the saltwith organic base include salts with trimethylamine, triethylamine,pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine,triethanolamine, cyclohexylamine, dicyclohexylamine,N,N′-dibenzylethylenediamine and the like. Preferable examples of thesalt with inorganic acid include salts with hydrochloric acid,hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and thelike. Preferable examples of the salt with organic acid include saltswith formic acid, acetic acid, trifluoroacetic acid, phthalic acid,fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid,succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid and the like. Preferable examples of the saltwith basic amino acid include salts with arginine, lysine, ornithine andthe like. Preferable examples of the salt with acidic amino acid includesalts with aspartic acid, glutamic acid and the like.

Of these, a pharmaceutically acceptable salt is preferable. For example,when a compound has an acidic functional group, examples thereof includeinorganic salts such as alkali metal salts (e.g., sodium salt, potassiumsalt etc.), alkaline earth metal salts (e.g., calcium salt, magnesiumsalt etc.) and the like, ammonium salt etc., and when a compound has abasic functional group, examples thereof include salts with inorganicacid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuricacid, phosphoric acid and the like, and salts with organic acid such asacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid,maleic acid, citric acid, succinic acid, methanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid and the like.

[Production Method]

The compound of the present invention and the starting compounds can beproduced by a method known per se, for example, by method shown in thefollowing scheme and the like. In the following, the “room temperature”generally means 0-40° C. and, unless otherwise specified, each symbol inthe chemical formulas described in the schemes is as defined above. Inthe formulas, each compound includes salts, and examples of such saltinclude those similar to the salts of the compound of the presentinvention and the like. The compound obtained in each step can be useddirectly as the reaction mixture or as a crude product for the nextreaction. It can also be isolated from a reaction mixture by aconventional method, and can be easily purified by a separation meanssuch as recrystallization, distillation, chromatography and the like.When the compound in the formula is commercially available, acommercially available product can also be used directly. When each ringin the formula (1) has a substituent, the corresponding precursor alsohas a similar substituent.

When the starting compound has an amino group, a carboxyl group, ahydroxy group or a heterocyclic group, these groups may be protected bya protecting group generally used in peptide chemistry and the like. Byremoving the protecting group as necessary after the reaction, theobjective compound can be obtained. The protection and deprotection canbe performed according to a method known per se, for example, the methoddescribed in “Protective Groups in Organic Synthesis, 3rd Ed”, JohnWiley and Sons, Inc. (1999) (Theodora W. Greene, Peter G. M. Wuts). Inthe following schemes, P¹ is a carboxy-protecting group, and P² is aprotecting group for the nitrogen atom of amine or amide, and theprotecting group known per se can be used. For example, P is preferablya benzyl group, a methyl group, an ethyl group, a tert-butyl group orthe like, and P² is preferably a tert-butoxycarbonyl group, abenzyloxycarbonyl group, a benzyl group or the like.

Examples of the “leaving group” for LG¹-LG⁴ include a halogen atom(e.g., a chlorine atom, a bromine atom, an iodine atom etc.), C₁₋₆alkylsulfonyloxy optionally substituted by halogen atom(s) (e.g., achlorine atom, a bromine atom, an iodine atom etc.) (e.g.,methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxyetc.), C₆₋₁₀ arylsulfonyloxy optionally substituted by C₁₋₆ alkylgroup(s) (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl,hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl,3,3-dimethylbutyl, 2-ethylbutyl etc.) (e.g., benzenesulfonyloxy,p-toluenesulfonyloxy etc.), C₁₋₆ alkylsulfonyl (e.g., methanesulfonyl,ethanesulfonyl etc.) and the like. In addition, a substituent capable ofconverting to a leaving group is encompassed in LG¹-LG⁴, and it can beconverted to a leaving group by a reaction known per se in a desiredstep. For example, when LG¹-LG⁴ is a methylthio group, it is convertedto a methanesulfonyl group by oxidation reaction.

The following each step can be performed without solvent, or bydissolving or suspending starting material compound in a suitablesolvent prior to the reaction. In this case, solvent may be used alone,or two or more kinds of these solvents may be mixed in an appropriateratio and used. Specific examples of the solvent used for the productionmethod of the compound of the present invention include the followings.

alcohols: methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol,2-methoxyethanol etc.

ethers: diethyl ether, diisopropyl ether, diphenyl ether,tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane etc. aromatichydrocarbons: benzene, chlorobenzene, toluene, xylene etc.

saturated hydrocarbons: cyclohexane, hexane etc. amides:N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphorictriamide etc. halogenated hydrocarbons: dichloromethane, chloroform,carbon tetrachloride, 1,2-dichloroethane etc. nitriles: acetonitrile,propionitrile etc. sulfoxides: dimethylsulfoxide etc. aromatic organicbases: pyridine, lutidine etc. acid anhydrides: acetic anhydride etc.organic acids: formic acid, acetic acid, propionic acid, trifluoroaceticacid, methanesulfonic acid etc. inorganic acids: hydrochloric acid,sulfuric acid etc. esters: methyl acetate, ethyl acetate, butyl acetateetc. ketones: acetone, methylethylketone etc.

Specific examples of the base or acid scavenger used for the productionmethod of the compound of the present invention include the followings.

inorganic bases: sodium hydroxide, potassium hydroxide, magnesiumhydroxide etc.

basic salts: sodium carbonate, potassium carbonate, cesium carbonate,calcium carbonate, sodium hydrogen carbonate etc.

organic bases: triethylamine, diisopropylethylamine, tributylamine,cyclohexyldimethylamine, pyridine, lutidine, 4-dimethylaminopyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine,N-methylmorpholine, 1,5-diazabicyclo[4.3.0]-5-nonene,1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]-7-undecene,imidazole etc.metal alkoxides: sodium methoxide, sodium ethoxide, potassiumtert-butoxide etc.alkali metal hydrides: sodium hydride, potassium hydride etc.metal amides: sodium amide, lithiumdiisopropylamide,lithiumhexamethyldisilazide etc.organic lithium reagents: methyllithium, n-butyllithium,sec-butyllithium, tert-butyllithium etc.

Specific examples of the acid or acid catalyst used for the productionmethod of the compound of the present invention include the followings.

inorganic acids: hydrochloric acid, sulfuric acid, nitric acid,hydrobromic acid, phosphoric acid etc.

organic acids: acetic acid, trifluoroacetic acid, oxalic acid, phthalicacid, fumaric acid, tartaric acid, maleic acid, citric acid, succinicacid, methanesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonicacid etc.

Lewis acid: boron trifluoride ether complex, zinc iodide, anhydrousaluminum chloride, anhydrous zinc chloride, anhydrous iron chloride etc.

Compound (I) can be synthesized, for example, according to ProductionMethod A, Production Method B or the like explained below.

The symbols in each scheme in the production method are as definedabove, unless otherwise specified. In each reaction in Production MethodA and B, R^(a) is a hydrogen atom or an optionally substituted C₁₋₆alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl,hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl,3,3-dimethylbutyl, 2-ethylbutyl etc.), or two R^(a) in combinationoptionally form a ring such as 4,4,5,5-tetramethyl-1,3,2-dioxaborolaneand the like.

[Production Method A]

wherein each symbol is as defined above.

The compound of the present invention can be produced by a sequence ofreaction steps of Step A-1 to Step A-4.

(Step A-1)

Compound (5) can be produced by reacting compound (2) with compound (3)or compound (4) (R³=4-pyrimidinyl). The reaction is carried out in thepresence of a metal catalyst. The metal catalyst is preferably apalladium compound [e.g., palladium(II) acetate,tetrakis(triphenylphosphine)palladium(0),dichlorobis(triphenylphosphine)palladium(II),dichlorobis(triethylphosphine)palladium(II),tris(dibenzylideneacetone)dipalladium(0), a complex of palladium(II)acetate and 1,1′-bis(diphenylphosphino)ferrocene, etc.]. The amount ofthe metal catalyst to be used is about 0.000001-1.0 mol per 1 mol ofcompound (2). The metal catalyst can be used together with a phosphineligand. The amount of the phosphine ligand to be used is about 0.01-5mol per 1 mol of compound (2). Examples of the phosphine ligand includetriphenylphosphine, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene,tri-tert-butylphosphine and the like. In addition, a salt such astri-tert-butylphosphine tetrafluoroborate can be used. The reaction isgenerally carried out in the presence of a base. Examples of the baseinclude inorganic bases, basic salts and the like. When desired, thereaction may be carried out by adding an additive such as copper(I)cyanide, copper(I) bromide and the like. The amount of compound (3) orcompound (4) to be used is about 0.8-10 mol per 1 mol of compound (2).The amount of the base to be used is about 1-20 mol per 1 mol ofcompound (2). The amount of the additive to be used is about0.000001-5.0 mol per 1 mol of compound (2). When a metal catalystunstable to oxygen is used for the reaction, the reaction is preferablycarried out in a stream of an inactive gas such as argon gas, nitrogengas and the like. This reaction is advantageously carried out in asolvent inert to the reaction. While the solvent is not particularlylimited as long as the reaction proceeds, preferable examples thereofinclude alcohols, ethers, aromatic hydrocarbons, saturated hydrocarbons,amides, halogenated hydrocarbons, nitriles, esters, water, mixedsolvents thereof and the like. While the reaction time varies dependingon the reagent or solvent to be used, it is generally 1 min-200 hr. Thereaction temperature is preferably 0-150° C. In addition, the reactioncan be carried out with irradiation of microwave in order to promote thereaction.

(Step A-2)

Compound (5) can also be produced by reacting compound (6) with compound(7). The reaction is carried out in the same manner as in Step A-1.

When desired, compound (5) produced in Step A-1 or Step A-2 can besubjected to a reduction step. For example, when compound (5) containsN-oxido or a halogen atom, it is removed by a reduction reaction knownper se using palladium carbon and the like.

(Step A-3)

Compound (8) can be produced by removing the protecting group P¹ ofcompound (5). The removal of the protecting group can be carried outaccording to a method known per se, for example, the method described in“Protective Groups in Organic Synthesis, 3rd Ed”, John Wiley and Sons,Inc. (1999) (Theodora W. Greene, Peter G. M. Wuts), or the like.

Compound (8) can also be produced according to a method known per se, ora method analogous thereto.

(Step A-4)

Compound (I) can be produced by reacting carboxylic acid (8) or areactive derivative thereof with compound (9). Examples of the reactivederivative of the carboxylic acid include acid halides such as acidchlorides, acid bromides and the like; acid amides with pyrazole,imidazole, benzotriazole and the like; mixed acid anhydrides with asacetic acid, propionic acid, butyric acid and the like; acid azides;activated esters such as diethoxyphosphate ester, diphenoxyphosphateester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, cyanomethyl ester,pentachlorophenyl ester, ester with N-hydroxysuccinimide, ester withN-hydroxyphthalimide, ester with 1-hydroxybenzotriazole, ester with6-chloro-1-hydroxybenzotriazole, ester with 1-hydroxy-1H-2-pyridone, andthe like; activated thioesters such as 2-pyridyl thioester,2-benzothiazolyl thioester and the like, and the like. Compound (I) canalso be produced by directly reacting carboxylic acid (8) with compound(9) in the presence of a suitable condensing agent, instead of using thereactive derivative. Examples of the condensing agent includeN,N′-disubstituted carbodiimides such as N,N′-dicyclohexylcarbodiimide,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSC) hydrochloride andthe like; azolides such as N,N′-carbonyldiimidazole and the like;dehydrating agents such asN-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, phosphorus oxychloride,alkoxyacetylene and the like; 2-halogenopyridiniums such as2-chloromethylpyridinium iodide, 2-fluoro-1-methylpyridinium iodide andthe like; phosphorylcyanides such as diethylphosphorylcyanide and thelike; 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (TATU) and the like. When a condensing agent is used,the reaction is considered to progress via a reactive derivative ofcarboxylic acid (8). The amount of carboxylic acid (8) or a reactivederivative thereof to be used is generally about 0.8-5 mol per 1 mol ofcompound (9). This reaction is advantageously carried out in a solventinert to the reaction. While the solvent is not particularly limited aslong as the reaction proceeds, preferable examples thereof includeethers, aromatic hydrocarbons, saturated hydrocarbons, amides,halogenated hydrocarbons, nitriles, sulfoxides, aromatic organic bases,mixed solvents thereof. The reaction can be carried out in the presenceof a basic salt, an organic bases or the like in order to promote thereaction. In addition, when an acidic substance is released due thereaction, a basic salt, an organic base and the like can be used inorder to remove it from the reaction system. While the reaction timevaries depending on the reagent or solvent to be used, it is generally10 min-72 hr. The reaction temperature is preferably 0-100° C.

[Production Method B]

wherein each symbol is as defined above.

Compound (I) can also be produced by a sequence of reaction steps ofStep B-1 to Step B-2.

(Step B-1)

Compound (11) can be produced by reacting carboxylic acid (10) or areactive derivative thereof with compound (9). The reaction can becarried out in the same manner as in Step A-4.

(Step B-2)

Compound (I) can be produced by reacting compound (11) with compound (3)or compound (4) (R³=4-pyrimidinyl). The reaction can be carried out inthe same manner as in Step A-1.

[Production Method C]

wherein M¹ is a magnesium atom and halogen atom moiety derived from theGrignard reagent, or a lithium atom moiety derived from the organiclithium reagent; and the other each symbols are as defined above.

Compound (9) may be a commercially available product, or can be producedby a sequence of reaction steps of Step C-1 to Step C-2. Alternatively,compound (9) can also be produced according to a method known per se ora method analogous thereto.

(Step C-1)

Compound (14) wherein R² is a hydrogen atom can be produced by reactingcompound (12) with an organic metal reagent (13). Examples of theorganic metal reagent include the Grignard reagents, organic lithiumreagents and the like. The amount of the organic metal reagent to beused is about 1-10 mol per 1 mol of compound (12). This reaction isadvantageously carried out in a solvent inert to the reaction. While thesolvent is not particularly limited as long as the reaction proceeds,preferable examples thereof include ethers, aromatic hydrocarbons,saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles,sulfoxides, mixed solvents thereof and the like. While the reaction timevaries depending on the reagent or solvent to be used, it is generally10 min-100 hr. The reaction temperature is preferably −78-50° C.

When desired, the obtained compound can be subjected to an alkylationstep. For example, the obtained compound can be reacted with a compoundrepresented by R^(2a)LG⁴ wherein R^(2a) is an optionally substitutedC₁₋₆ alkyl group, in the presence of a base.

(Step C-2)

Compound (9) can be produced by removing the protecting group P² ofcompound (14). The removal of the protecting group can be carried outaccording to a method known per se, for example, the method described in“Protective Groups in Organic Synthesis, 3rd Ed”, John Wiley and Sons,Inc. (1999) (Theodora W. Greene, Peter G. M. Wuts), or the like.

The starting compound and/or the production intermediate for theaforementioned compound (I) may form a salt, which is not particularlylimited as long as the reaction can be performed and, for example, thosesimilar to the salts optionally formed by the aforementioned compound(I) and the like, and the like are used.

As for the configuration isomers (E, Z forms) of compound (I), they canbe isolated and purified when isomerization occurs by, for example, ageneral separation means such as extraction, recrystallization,distillation, chromatography and the like, and a pure compound can beproduced. In addition, it is also possible to isomerize a double bond bythe methods described in Jikken Kagaku Kouza (Courses in ExperimentalChemistry) 14 (The Chemical Society of Japan ed.), pages 251 to 253, 4thEdition Jikken Kagaku Kouza 19 (The Chemical Society of Japan ed.),pages 273 to 274 or a method according thereto, using heating, an acidcatalyst, a transition metal complex, a metal catalyst, a radicalcatalyst, light irradiation or a strong base catalyst and the like, andobtain the corresponding pure isomer.

When desired, compound (I) can be synthesized by performingdeprotection, acylation reaction, alkylation reaction, hydrogenationreaction, oxidation reaction, reduction reaction, carbon chain extensionreaction, and substituent exchange reaction singly or two or morethereof in combination.

In each of the above-mentioned reactions, when the compound has afunctional group such as an amino group, a carboxyl group or a hydroxygroup, the reaction can be carried out after a protecting groupgenerally used in peptide chemistry and the like is introduced intothese groups. By removing the protecting group as necessary after thereaction, the objective compound can be obtained.

Examples of the protecting group include formyl; C₁₋₆ alkyl-carbonyl(e.g., acetyl, propionyl etc.), phenylcarbonyl, C₁₋₆ alkoxy-carbonyl(e.g., methoxycarbonyl, ethoxycarbonyl etc.), phenyloxycarbonyl, C₇₋₁₀aralkyloxy-carbonyl (e.g., benzyloxycarbonyl etc.), trityl, phthaloyland the like, each of which is optionally substituted. Examples of thesubstituent include a halogen atom (e.g., fluorine, chlorine, bromine,iodine etc.), C₁₋₆ alkyl-carbonyl (e.g., acetyl, propionyl, valeryletc.), nitro and the like. The number of substituents is, for example, 1to 3.

The removal method of the protecting group can be carried out accordingto a method known per se, and for example, a method using acid, base,ultraviolet rays, hydrazine, phenylhydrazine, sodiumN-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetateand the like, a reduction method, and the like can be employed.

The thus-obtained compound (I), other reaction intermediate therefor andstarting compounds thereof can be isolated and purified from a reactionmixture according to a method known per se, for example, extraction,concentration, neutralization, filtration, distillation,recrystallization, column chromatography, thin layer chromatography,preparative high performance liquid chromatography (preparative HPLC),moderate-pressure preparative liquid chromatography (moderate-pressurepreparative LC) and the like.

A salt of compound (I) can be produced by a method known per se. Forexample, when compound (I) is a basic compound, it can be produced byadding an inorganic acid or organic acid, or when compound (I) is anacidic compound, by adding an organic base or inorganic base.

Compound (I) may be a prodrug, and the prodrug of compound (I) refers toa compound which is converted to compound (I) as a result of a reactionwith an enzyme, gastric acid, etc. under physiological conditions invivo, thus a compound that undergoes enzymatic oxidation, reduction,hydrolysis etc. to convert to compound (I) and a compound that undergoeshydrolysis and the like by gastric acid, etc. to convert to compound(I).

Examples of the prodrug for compound (I) include

(1) a compound obtained by subjecting an amino group in compound (I) toacylation, alkylation or phosphorylation (e.g., a compound obtained bysubjecting an amino group in compound (I) to eicosanoylation,alanylation, pentylaminocarbonylation,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylation,tetrahydrofurylation, pyrrolidylmethylation, pivaloyloxymethylation,tert-butylation, ethoxycarbonylation, tert-butoxycarbonylation,acetylation, cyclopropylcarbonylation);(2) a compound obtained by subjecting a hydroxy group in compound (I) toacylation, alkylation, phosphorylation or boration (e.g., a compoundobtained by subjecting a hydroxy group in compound (I) to acetylation,palmitoylation, propanoylation, pivaloylation, succinylation,fumarylation, alanylation or dimethylaminomethylcarbonylation);(3) a compound obtained by subjecting a carboxyl group in compound (I)to esterification or amidation (e.g., a compound obtained by subjectinga carboxyl group in compound (I) to ethylesterification,phenylesterification, carboxymethylesterification,dimethylaminomethylesterification, pivaloyloxymethylesterification,ethoxycarbonyloxyethylesterification, phthalidylesterification,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methylesterification,cyclohexyloxycarbonylethylesterification or methylamidation) and thelike. Any of these compounds can be produced from compound (I) accordingto a method known per se.

A prodrug of compound (I) may also be one which is converted to compound(I) under physiological conditions as described in “IYAKUHIN no KAIHATSU(Development of Pharmaceuticals)”, Vol. 7, Design of Molecules, p.163-198, Published by HIROKAWA SHOTEN (1990).

In the present specification, compound (I), and a prodrug thereof aresometimes collectively abbreviated as “the compound of the presentinvention”.

When compound (I) has isomers such as optical isomer, stereoisomer,positional isomer, rotamer and the like, such isomers and a mixturethereof are also encompassed in compound (I). For example, when compound(I) has optical isomers, an optical isomer resolved from this compoundis also encompassed in compound (I). These isomers can be obtained as asingle product according to synthesis methods or separation methodsknown per se (e.g., concentration, solvent extraction, columnchromatography, recrystallization, etc.).

Compound (I) may be a crystal, and a single crystal form and a mixtureof crystal forms are both encompassed in compound (I). The crystal canbe produced by crystallizing according to a crystallization method knownper se.

Compound (I) may be a hydrate, a non-hydrate, a solvate or anon-solvate.

Compound (I) may be labeled with an isotope (e.g., ³H, ¹¹C, ¹⁴C, ¹⁸F,³⁵S, ¹²⁵I etc.) and the like.

Compound (I) also encompasses a deuterium conversion form wherein ¹H isconverted to ²H(D).

Compound (I) may be a pharmaceutically acceptable cocrystal or a saltthereof. The cocrystal or a salt thereof means a crystalline substanceconstituted with two or more special solids at room temperature, eachhaving different physical properties (e.g., structure, melting point,melting heat, hygroscopicity, solubility and stability etc.). Thecocrystal or a salt thereof can be produced according to acocrystallization a method known per se.

Compound (I) may also be used as a PET tracer.

The compound of the present invention has low toxicity, and can be usedas it is or in the form of a pharmaceutical composition by mixing with apharmacologically acceptable carrier etc. to mammals (e.g., human,mouse, rat, rabbit, dog, cat, bovine, horse, swine, monkey) as an agentfor the prophylaxis or treatment of various diseases mentioned below.

As pharmacologically acceptable carriers, various organic or inorganiccarrier substances conventionally used as preparation materials can beused. These are incorporated as excipient, lubricant, binder anddisintegrant for solid preparations, or solvent, solubilizing agent,suspending agent, isotonicity agent, buffer and soothing agent forliquid preparations, and the like, and preparation additives such aspreservative, antioxidant, colorant, sweetening agent and the like canbe added as necessary.

Preferable examples of the excipient include lactose, sucrose,D-mannitol, D-sorbitol, starch, gelatinated starch, dextrin, crystallinecellulose, low-substituted hydroxypropylcellulose, sodiumcarboxymethylcellulose, gum arabic, pullulan, light anhydrous silicicacid, synthesis aluminum silicate and magnesium alumino metasilicate.

Preferable examples of the lubricant include magnesium stearate, calciumstearate, talc and colloidal silica.

Preferable examples of the binder include gelatinated starch, sucrose,gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodiumcarboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol,trehalose, dextrin, pullulan, hydroxypropylcellulose,hydroxypropylmethylcellulose and polyvinylpyrrolidone.

Preferable examples of the disintegrant include lactose, sucrose,starch, carboxymethylcellulose, calcium carboxymethylcellulose,croscarmellose sodium, sodium carboxymethyl starch, light anhydroussilicic acid and low-substituted hydroxypropylcellulose.

Preferable examples of the solvent include water for injection,physiological brine, Ringer's solution, alcohol, propylene glycol,polyethylene glycol, sesame oil, corn oil, olive oil and cottonseed oil.

Preferable examples of the solubilizing agents include polyethyleneglycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate,ethanol, trisaminomethane, cholesterol, triethanolamine, sodiumcarbonate, sodium citrate, sodium salicylate and sodium acetate.

Preferable examples of the suspending agent include surfactants such asstearyltriethanolamine, sodium lauryl sulfate, lauryl aminopropionate,lecithin, benzalkonium chloride, benzethonium chloride, glycerolmonostearate and the like; hydrophilic polymers such as polyvinylalcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose,methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,hydroxypropylcellulose and the like; polysorbates; and polyoxyethylenehydrogenated castor oil.

Preferable examples of the isotonicity agent include sodium chloride,glycerol, D-mannitol, D-sorbitol and glucose.

Preferable examples of the buffer include buffers such as phosphate,acetate, carbonate, citrate and the like.

Preferable examples of the soothing agent include benzyl alcohol.

Preferable examples of the preservative include p-oxybenzoates,chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid andsorbic acid.

Preferable examples of the antioxidant include sulfite and ascorbate.

Preferable examples of the colorant include aqueous water-soluble foodtar colors (e.g., food colors such as Food Color Red Nos. 2 and 3, FoodColor Yellow Nos. 4 and 5, Food Color Blue Nos. 1 and 2 and the likefood colors), water insoluble lake dyes (e.g., aluminum salt of theaforementioned water-soluble food tar color) and natural dyes (e.g.,3-carotene, chlorophyll, ferric oxide red).

Preferable examples of the sweetening agent include saccharin sodium,dipotassium glycyrrhizinate, aspartame and stevia.

Examples of the dosage form of the pharmaceutical composition includeoral preparations such as tablet (including sugar-coated tablet,film-coated tablet, sublingual tablet, orally disintegrating tablet),capsules (including soft capsule, microcapsule), granule, powder,troche, syrup, emulsion, suspension, films (e.g., orally disintegrablefilms) and the like; and parenteral agents such as injection (e.g.,subcutaneous injection, intravenous injection, intramuscular injection,intraperitoneal injection, drip infusion), external preparations (e.g.,dermal preparation, ointment), suppository (e.g., rectal suppository,vaginal suppository), pellet, nasal preparation, pulmonary preparation(inhalant), eye drop and the like.

These can be respectively safely administered orally or parenterally(e.g., topically, rectally, intravenously administered).

These preparations may be a release control preparation (e.g.,sustained-release microcapsule) such as an immediate-releasepreparation, a sustained-release preparation and the like.

The pharmaceutical composition can be produced according to a methodconventionally used in the field of pharmaceutical formulation, forexample, the method described in the Japanese Pharmacopoeia, and thelike.

While the content of the compound of the present invention in thepharmaceutical composition varies depending on the dosage form, dose ofthe compound of the present invention and the like, it is, for example,about 0.1 to 100 wt %.

During production of an oral preparation, coating may be applied asnecessary for the purpose of masking of taste, enteric property ordurability.

Examples of the coating base to be used for coating include sugarcoating base, water-soluble film coating base, enteric film coating baseand sustained-release film coating base.

As the sugar coating base, sucrose is used. Moreover, one or more kindsselected from talc, precipitated calcium carbonate, gelatin, gum arabic,pullulan, carnauba wax and the like may be used in combination.

Examples of the water-soluble film coating base include cellulosepolymers such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose,hydroxyethyl cellulose, methylhydroxyethyl cellulose etc.; syntheticpolymers such as polyvinylacetal diethylaminoacetate, aminoalkylmethacrylate copolymer E [Eudragit E (trade name)], polyvinylpyrrolidoneetc.; and polysaccharides such as pullulan etc.

Examples of the enteric film coating base include cellulose polymerssuch as hydroxypropylmethyl cellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethyl cellulose, celluloseacetate phthalate etc.; acrylic polymers such as methacrylic acidcopolymer L [Eudragit L (trade name)], methacrylic acid copolymer LD[Eudragit L-30D55 (trade name)], methacrylic acid copolymer S [EudragitS (trade name)] etc.; and naturally occurring substances such as shellacetc.

Examples of the sustained-release film coating base include cellulosepolymers such as ethyl cellulose etc.; and acrylic polymers such asaminoalkyl methacrylate copolymer RS [Eudragit RS (trade name)], ethylacrylate-methyl methacrylate copolymer suspension [Eudragit NE (tradename)] etc.

The above-mentioned coating bases may be used after mixing with two ormore kinds thereof at appropriate ratios. For coating, for example, alight shielding agent such as titanium oxide, red ferric oxide and thelike can be used.

The compound of the present invention shows low toxicity (e.g., acutetoxicity, chronic toxicity, genetic toxicity, reproductive toxicity,cardiotoxicity, carcinogenicity) and a few side effects. Therefore, itcan be used as an agent for the prophylaxis or treatment or a diagnosticof various diseases in a mammal (e.g., human, bovine, horse, dog, cat,monkey, mouse, rat).

The compound of the present invention has a superior CH24H inhibitoryaction and can suppress nerve cell death, Aβ increase, intracerebralinflammation and the like.

Accordingly, the compound of the present invention is useful for theprophylaxis, improvement of symptoms, suppression of progression ortreatment of diseases involving enhanced function of CH24H, for example,neurodegenerative disease.

In the present specification, the “neurodegenerative disease” means adisease associated with denaturation of neural tissues.

Specific examples of the neurodegenerative disease include Alzheimer'sdisease, mild cognitive impairment, Huntington's disease, Parkinson'sdisease, amyotrophic lateral sclerosis, traumatic brain injury, cerebralinfarction, glaucoma, multiple sclerosis and the like.

In addition, the compound of the present invention is useful for theprophylaxis, improvement of symptoms, suppression of progression ortreatment of diseases involving enhanced function of CH24H, for example,epilepsy, schizophrenia and the like.

Moreover, the compound of the present invention is useful for theprophylaxis, improvement of symptoms, suppression of progression ortreatment of diseases involving enhanced function of CH24H, for example,spasm and the like.

The dose of the compound of the present invention varies depending onthe administration subject, route of administration, target disease,symptoms, etc. For example, when it is administered orally to an adultpatient (body weight 60 kg), its dose is about 0.01 to 100 mg/kg bodyweight per dose, preferably 0.05 to 30 mg/kg body weight per dose, morepreferably 0.1 to 10 mg/kg body weight per dose and this amount isdesirably administered in 1 to 3 portions daily.

When the compound of the present invention is applied to each of theabove-mentioned diseases, it can be used in an appropriate combinationwith a medicament or a treatment method generally employed for thedisease.

Examples of the medicament (hereinafter to be abbreviated as“concomitant drug”) to be used in combination with the compound of thepresent invention include acetylcholine esterase inhibitors (e.g.,donepezil, rivastigmine, galanthamine, zanapezil etc.), antidementianagents (e.g., memantine), inhibitors of β amyloid protein production,secretion, accumulation, coagulation and/or deposition, β secretaseinhibitors (e.g., 6-(4-biphenylyl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin,6-(4-biphenylyl)methoxy-2-(N,N-dimethylamino)methyltetralin,6-(4-biphenylyl)methoxy-2-(N,N-dipropylamino)methyltetralin,2-(N,N-dimethylamino)methyl-6-(4′-methoxybiphenyl-4-yl)methoxytetralin,6-(4-biphenylyl)methoxy-2-[2-(N,N-diethylamino)ethyl]tetralin,2-[2-(N,N-dimethylamino)ethyl]-6-(4′-methylbiphenyl-4-yl)methoxytetralin,2-[2-(N,N-dimethylamino)ethyl]-6-(4′-methoxybiphenyl-4-yl)methoxytetralin,6-(2′,4′-dimethoxybiphenyl-4-yl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin,6-[4-(1,3-benzodioxol-5-yl)phenyl]methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin,6-(3′,4′-dimethoxybiphenyl-4-yl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin,an optically active form thereof, a salt thereof and a hydrate thereof,OM99-2 (WO01/00663)), γ secretase inhibitory agent, β amyloid proteincoagulation inhibitory agent (e.g., PTI-00703, ALZHEMED (NC-531),PPI-368 (JP-A-11-514333), PPI-558 (JP-A-2001-500852), SKF-74652(Biochem. J. (1999), 340(1), 283-289)), β amyloid vaccine, β amyloiddegrading enzyme and the like, cerebral function activators (e.g.,aniracetam, nicergoline), other therapeutic drug for Parkinson's disease[(e.g., dopamine receptor agonists (e.g., L-DOPA, bromocriptine,pergolide, talipexole, pramipexole, Cabergoline, adamantadine), amonoamine oxidase (MAO) inhibitors (e.g., deprenyl, Selgiline(selegiline), remacemide, riluzole), anticholinergic agents (e.g.,trihexyphenidyl, biperiden), COMT inhibitors (e.g., entacapone)],therapeutic drug for amyotropic lateral sclerosis (e.g., riluzole etc.,neurotrophic factor), therapeutic drug for abnormal behavior, wanderingand the like due to the progress of dementia (e.g., sedative drug,antianxiety drug), apoptosis inhibitors (e.g., CPI-1189, IDN-6556,CEP-1347), neuronal differentiation or regeneration promoters (e.g.,leteprinim, xaliproden (SR-57746-A), SB-216763, Y-128, VX-853,prosaptide,5,6-dimethoxy-2-[2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl]isoindoline,5,6-dimethoxy-2-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]isoindoline,6-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]-6,7-dihydro-5H-[1,3]dioxolo[4,5-f]isoindoleand optically active forms, salts and hydrates thereof), antidepressants(e.g., desipramine, amitriptyline, imipramine, tramadol), antiepilepsydrug (e.g., lamotrigine), antianxiety drugs (e.g., benzodiazepine),non-steroidal anti-inflammatory drugs (e.g., meloxicam, tenoxicam,indomethacin, ibuprofen, celecoxib, rofecoxib, aspirin, indomethacin),disease-modifying anti-rheumatic drugs (DMARDs), anti-cytokine drugs(e.g., TNF inhibitor, MAP kinase inhibitor), steroidal drugs (e.g.,dexamethasone, hexestrol, cortisone acetate), therapeutic agents forincontinence or frequent urination (e.g., flavoxate hydrochloride,oxybutynin hydrochloride, propiverine hydrochloride), phosphodiesteraseinhibitors (e.g., sildenafil (citrate)), dopamine agonists (e.g.,apomorphine etc.), antiarrhythmics (e.g., mexiletine), sex hormones orderivatives thereof (e.g., progesterone, estradiol, estradiol benzoate),therapeutic agents for osteoporosis (e.g., alfacalcidol, calcitriol,elcatonin, calcitonin salmon, estriol, ipriflavone, disodiumpamidronate, sodium alendronate hydrate, disodium incadronate),parathyroid hormone (PTH), calcium receptor antagonists, therapeuticdrugs for insomnia (e.g., benzodiazepine medicament, non-benzodiazepinemedicament, melatonin agonist), therapeutic drugs for schizophrenia(e.g., typical antipsychotic agents such as haloperidol and the like;atypical antipsychotic agents such as clozapine, olanzapine,risperidone, aripiprazole and the like; medicament acted on metabotropicglutamate receptor or ionic channel-conjugated glutamate receptor;phosphodiesterase inhibitor) and the like.

In addition, a combined use with a transplantation method of neural stemcell or neural precursor cell prepared from embryonic stem cell ornervous tissue, or fetal neural tissue, and a combined use with apharmaceutical agent such as an immunosuppressant after thetransplantation and the like.

Furthermore, the compound of the present invention may be used incombination with the following concomitant drugs.

(1) Therapeutic Agent for Diabetes

For example, insulin preparations (e.g., animal insulin preparationextracted from the pancreas of bovine, swine; human insulin preparationgenetically synthesized using Escherichia coli, yeast; zinc insulin;protamine zinc insulin; insulin fragment or derivatives (e.g., INS-1),oral insulin preparation), insulin sensitizer (e.g., pioglitazone or asalt thereof (preferably hydrochloride), rosiglitazone or a salt thereof(preferably maleate), Tesaglitazar, Ragaglitazar, Muraglitazar,Edaglitazone, Metaglidasen, Naveglitazar, AMG-131, THR-0921),α-glucosidase inhibitor (e.g., voglibose, acarbose, miglitol,emiglitate), biguanide (e.g., metformin, buformin or a salt thereof(e.g., hydrochloride, fumarate, succinate)), insulin secretagogue[sulfonylurea (e.g., tolbutamide, glibenclamide, gliclazide,chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride,glipizide, glybuzole), repaglinide, nateglinide, mitiglinide or calciumsalt hydrate thereof, glucose-dependent insulin secretagogue (e.g.,[(3S)-6-({2′,6′-dimethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]aceticacid or a salt thereof)], dipeptidyl peptidase IV inhibitor (e.g.,Alogliptin, Vildagliptin, Sitagliptin, Saxagliptin, T-6666, TS-021), β3agonist (e.g., AJ-9677), GPR40 agonist, GLP-1 receptor agonist [e.g.,GLP-1, GLP-1MR agent, NN-2211, AC-2993 (exendin-4), BIM-51077,Aib(8,35)hGLP-1(7,37)NH₂, CJC-1131], amylin agonist (e.g., pramlintide),phosphotyrosine phosphatase inhibitors (e.g., sodium vanadate),gluconeogenesis inhibitor (e.g., glycogen phosphorylase inhibitor,glucose-6-phosphatase inhibitors, glucagon antagonists), SGLUT(sodium-glucose cotransporter) inhibitor (e.g., T-1095),11-hydroxysteroid dehydrogenase inhibitor (e.g., BVT-3498), adiponectinor an agonist thereof, IKK inhibitor (e.g., AS-2868), leptin resistanceimproving drugs, somatostatin receptor agonists, glucokinase activators(e.g., Ro-28-1675), GIP (Glucose-dependent insulinotropic peptide) andthe like.

(2) Therapeutic Agents for Diabetic Complications

For example, aldose reductase inhibitors (e.g., tolrestat, epalrestat,zenarestat, zopolrestat, minalrestat, fidarestat, CT-112), neurotrophicfactor and an increasing agent thereof (e.g., NGF, NT-3, BDNF,neurotrophic factors and increasing drugs described in WO01/14372 (e.g.,4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-methylphenoxy)propyl]oxazole)),nerve regeneration promoting agent (e.g., Y-128), PKC inhibitor (e.g.,ruboxistaurin mesylate), AGE inhibitor (e.g., ALT946, pimagedine,pyratoxanthine, N-phenacylthiazolium bromide (ALT766), ALT-711, EXO-226,Pyridorin, pyridoxamine), active oxygen scavengers (e.g., thiocticacid), cerebral vasodilator (e.g., tiapuride, mexiletine), somatostatinreceptor agonists (e.g., BIM23190), apoptosis signal regulatingkinase-1(ASK-1) inhibitor and the like can be mentioned.

(3) Therapeutic Agent for Hyperlipidemia

For example, statin compound (e.g., pravastatin, simvastatin,lovastatin, atorvastatin, fluvastatin, rosuvastatin, pitavastatin, or asalt thereof (e.g., sodium salt, calcium salt)), squalene synthaseinhibitors (e.g., lapaquistat acetate or a salt thereof), fibratecompound (e.g., bezafibrate, clofibrate, simfibrate, clinofibrate), ACATinhibitor (e.g., Avasimibe, Eflucimibe), anion exchange resin (e.g.,colestyramine), probucol, nicotinic acid drug (e.g., nicomol,niceritrol), ethyl icosapentate, phytosterol (e.g., soysterol, gammaoryzanol) and the like.

(4) Antihypertensive Agent

For example, angiotensin converting enzyme inhibitor (e.g., captopril,enalapril, delapril), angiotensin II antagonist (e.g., candesartancilexetil, losartan, eprosartan, valsartan, telmisartan, irbesartan,tasosartan,1-[[2′-(2,5-dihydro-5-oxo-4H-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]-2-ethoxy-1H-benzimidazole-7-carboxylicacid, Azilsartan, Azilsartan medoxomil), calcium antagonist (e.g.,manidipine, nifedipine, amlodipine, efonidipine, nicardipine), potassiumchannel opener (e.g., levcromakalim, L-27152, AL 0671, NIP-121),clonidine and the like.

(5) Antiobesity Agent

For example, central-acting antiobesity agent (e.g., dexfenfluramine,fenfluramine, phentermine, sibutramine, amfepramone, dexamphetamine,mazindol, phenylpropanolamine, clobenzorex; MCH receptor antagonists(e.g., SB-568849; SNAP-7941; compounds described in WO01/82925 andWO01/87834); neuropeptide Y antagonist (e.g., CP-422935); cannabinoidreceptor antagonists (e.g., SR-141716, SR-147778); ghrelin antagonist;11β-hydroxysteroid dehydrogenase inhibitor (e.g., BVT-3498)), pancreaticlipase inhibitors (e.g., orlistat, cetilistat), β3 agonist (e.g.,AJ-9677, AZ40140), anorectic peptides (e.g., leptin, CNTF (ciliaryneurotrophic factor)), cholecystokinin agonist (e.g., lintitript,FPL-15849), anorexigenic agent (e.g., P-57) and the like.

(6) Diuretic

For example, xanthine derivative (e.g., theobromine sodium salicylate,theobromine calcium salicylate), thiazide preparation (e.g., ethiazide,cyclopenthiazide, trichloromethyazide, hydrochlorothiazide,hydroflumethiazide, benzylhydrochlorothiazide, penflutizide,polythiazide, methyclothiazide), antialdosterone preparation (e.g.,spironolactone, triamterene), carbonic anhydrase inhibitors (e.g.,acetazolamide), chlorobenzenesulfonamide agent (e.g., chlortalidone,mefruside, indapamide), azosemide, isosorbide, ethacrynic acid,piretanide, bumetanide, furosemide and the like.

(7) Chemotherapeutic Agent

For example, alkylating agents (e.g., cyclophosphamide, ifosfamide),metabolic antagonists (e.g., methotrexate, 5-fluorouracil or derivativethereof), antitumor antibiotics (e.g., mitomycin, adriamycin),plant-derived antitumor agents (e.g., vincristine, vindesine, Taxol),cisplatin, carboplatin, etoposide and the like. Of these, Furtulon andNeoFurtulon, which are 5-fluorouracil derivatives, and the like arepreferable.

(8) Immunotherapeutic Agent

For example, microorganism or bacterial components (e.g., muramyldipeptide derivative, Picibanil), polysaccharides having immunitypotentiating activity (e.g., lentinan, schizophyllan, krestin),cytokines obtained by genetic engineering techniques (e.g., interferon,interleukin (IL)), colony stimulating factors (e.g., granulocyte colonystimulating factor, erythropoietin) and the like, with preference givento interleukins such as IL-1, IL-2, IL-12 and the like.

(9) Antithrombotic Agent

For example, heparin (e.g., heparin sodium, heparin calcium, dalteparinsodium), warfarin (e.g., warfarin potassium), anti-thrombin drug (e.g.,argatroban), thrombolytic agent (e.g., urokinase, tisokinase, alteplase,nateplase, monteplase, pamiteplase), platelet aggregation inhibitor(e.g., ticlopidine hydrochloride, cilostazol, ethyl icosapentate,beraprost sodium, sarpogrelate hydrochloride) and the like.

(10) Cachexia Improving Medicament

For example, cyclooxygenase inhibitors (e.g., indomethacin etc.) [CancerResearch, Vol. 49, pages 5935-5939, 1989], progesterone derivatives(e.g., megestrol acetate) [Journal of Clinical Oncology, Vol. 12, pages213-225, 1994], glucosteroids (e.g., dexamethasone etc.), metoclopramideagents, tetrahydrocannabinol agents (publications are all as mentionedabove), fat metabolism improving agents (e.g., eicosapentanoic acidetc.) [British Journal of Cancer, Vol. 68, pages 314-318, 1993], growthhormones, IGF-1, or antibodies to a cachexia-inducing factor such asTNF-α, LIF, IL-6, oncostatin M and the like.

Two or more kinds of the above-mentioned concomitant drugs may be usedin combination at an appropriate ratio.

It is also possible to apply compound of the present invention to eachof the above-mentioned diseases in combination with a biologic (e.g.,antibody, vaccine preparation and the like), or as a combination therapyin combination with gene therapy method and the like.

Examples of the antibody and vaccine preparation include vaccinepreparation to angiotensin II, vaccine preparation to CETP, CETPantibody, TNFα antibody and antibody to other cytokine, amyloid βvaccine preparation, type 1 diabetes vaccine (e.g., DIAPEP-277manufactured by Peptor Ltd.), anti-HIV antibody, HIV vaccine preparationand the like, antibody or vaccine preparation to cytokine,renin-angiotensin enzyme and a product thereof, antibody or vaccinepreparation to enzyme or protein involved in blood lipid metabolism,antibody or vaccine to enzyme or protein involved in blood coagulationor fibrinolytic system, antibody or vaccine preparation to proteininvolved in saccharometabolism or insulin resistance and the like.

In addition, a combined use with a biological preparation involved in agrowth factor such as GH, IGF and the like is possible.

Examples of the gene therapy method include a treatment method using agene relating to cytokine, renin-angiotensin enzyme and a productthereof, G protein, G protein conjugated receptor and itsphosphorylation enzyme, a treatment method using a DNA decoy such asNFκB decoy and the like, a treatment method using an antisense, atreatment method using a gene relating to an enzyme or protein involvedin blood lipid metabolism (e.g., gene relating to metabolism, excretionor absorption of cholesterol or triglyceride or HDL-cholesterol or bloodphospholipid), a treatment method using a gene relating to an enzyme orprotein involved in angiogenesis therapy targeting obstruction ofperipheral vessel and the like (e.g., growth factors such as HGF, VEGFetc.), a treatment method using a gene relating to a protein involved insaccharometabolism or insulin resistance, an antisense to cytokine suchas TNF and the like, and the like.

In addition, it is possible to use in combination with various organregeneration methods such as heart regeneration, kidney regeneration,pancreas regeneration, blood vessel regeneration and the like or celltransplantation therapy utilizing bone marrow cell (myelomonocytic cell,myeloid stem cell) or an artificial organ utilizing tissue engineering(e.g., artificial blood vessel and cardiac muscle cell sheet).

The time of administration of the compound of the present invention andthat of the concomitant drug are not limited, and they may beadministered simultaneously or in a staggered manner to theadministration subject. Furthermore, the compound of the presentinvention and the concomitant drug may be administered as two kinds ofpreparations containing each active ingredient, or a single preparationcontaining both active ingredients.

The dose of the concomitant drug can be appropriately determined basedon the dose employed in clinical situations. The mixing ratio of thecompound of the present invention and a concomitant drug can beappropriately determined depending on the administration subject,administration route, target disease, symptom, combination and the like.When the subject of administration is human, for example, a concomitantdrug can be used in 0.01-100 parts by weight relative to 1 part byweight of the compound of the present invention.

EXAMPLES

The present invention is explained in detail in the following byreferring to Examples, Experimental Examples and Formulation Examples,which are not to be construed as limitative, and the invention may bechanged within the scope of the present invention.

In the following Examples, the “room temperature” generally means about10° C. to about 35° C. The ratios indicated for mixed solvents arevolume mixing ratios, unless otherwise specified. % means wt %, unlessotherwise specified.

In silica gel column chromatography, NH means use ofaminopropylsilane-bound silica gel. In HPLC (high performance liquidchromatography), C18 means use of octadecyl-bound silica gel. The ratiosof elution solvents are volume mixing ratios, unless otherwisespecified.

The abbreviations used in the specification mean the following.

THF: tetrahydrofuran

DME: 1,2-dimethoxyethane

DMF: N,N-dimethylformamide

DMA: N,N-dimethylacetamide

DMSO: dimethyl sulfoxide

ESI: electrospray method

APCI: atmospheric chemical ionization

[M+H]⁺: molecular ion peak

M: mol concentration

N: N concentration

IPE: diisopropyl ether

HATU: 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uroniumhexafluorophosphate

DMTMM: dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride

HPLC: high performance liquid chromatography

TFA: trifluoroacetic acid

mp: melting point

¹H NMR (protone nuclear magnetic resonance spectrum) was measured byFourier-transform type NMR. For the analysis, ACD/SpecManager (tradename) and the like were used. Peaks with very mild protons such as ahydroxy group, an amino group and the like are note described.

MS (mass spectrum) was measured by LC/MS (liquid chromatography massspectrometer). As the ionization method, ESI (ElectroSpray Ionization)method, or APCI (Atomospheric Pressure Chemical Ionization) method wasused. The data indicates those found. Generally, a molecular ion peak isobserved. In the case of a compound having a tert-butoxycarbonyl group(-Boc), a peak after elimination of a tert-butoxycarbonyl group ortert-butyl group may be observed as a fragment ion. In the case of acompound having a hydroxy group (—OH), a peak after elimination of H₂Omay be observed as a fragment ion. In the case of a salt, a molecularion peak or fragment ion peak of free form is generally observed.

The elemental analysis value (Anal.) shows Calculated value (Calcd) andFound value (Found).

Example 1 (4-benzyl-4-hydroxypiperidin-1-yl)(5-methyl-2-(pyridin-4-yl)phenyl)methanone A) methyl5-methyl-2-(pyridin-4-yl)benzoate

A mixture of methyl 2-bromo-5-methylbenzoate (5.2 g), pyridine-4-boronicacid (4.2 g), sodium carbonate (4.8 g),tetrakis(triphenylphosphine)palladium(0) (1.3 g), water (10 mL) and DME(50 mL) was heated under reflux overnight under a nitrogen atmosphere.The reaction mixture was diluted with ethyl acetate, and filteredthrough silica gel. The filtrate was concentrated under reducedpressure, and the residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (2.5g).

¹H NMR (300 MHz, CDCl₃) δ 2.45 (3H, s), 3.65 (3H, s), 7.18-7.25 (3H, m),7.39 (1H, d, J=7.9 Hz), 7.73 (1H, s), 8.59-8.64 (2H, m).

B) 5-methyl-2-(pyridin-4-yl)benzoic acid hydrochloride

A mixture of methyl 5-methyl-2-(pyridin-4-yl)benzoate (8.8 g), 6 Nhydrochloric acid (65 mL) and acetic acid (100 mL) was heated underreflux overnight. The solvent was evaporated under reduced pressure, andthe obtained solid was washed with ethyl acetate to give the titlecompound (6.6 g).

MS (APCI+): [M+H]⁺ 214.3.

C) (4-benzyl-4-hydroxypiperidin-1-yl)(5-methyl-2-(pyridin-4-yl)phenyl)methanone

A suspension of 5-methyl-2-(pyridin-4-yl)benzoic acid hydrochloride(0.33 g), 4-benzyl-4-hydroxypiperidine (0.38 g), HATU (0.75 g) andtriethylamine (0.92 mL) in DMF (5.0 mL) was stirred overnight at roomtemperature. The reaction mixture was diluted with water, and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine, and dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (NH, ethyl acetate/hexane), and thenpurified by preparative HPLC (C18, mobile phase: water/acetonitrile(containing 0.1% TFA)), the obtained fraction was concentrated underreduced pressure. To the residue was added saturated aqueous sodiumhydrogen carbonate solution, and the mixture was extracted with ethylacetate. The extract was dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The obtained solid wasrecrystallized from ethyl acetate/hexane to give the title compound(0.33 g).

¹H NMR (400 MHz, DMSO-d₆) δ 0.01-1.13 (2H, m), 1.22-1.49 (2H, m),2.20-2.47 (4H, m), 2.56-2.78 (2H, m), 2.82-3.09 (2H, m), 4.09-4.29 (1H,m), 4.31-4.39 (1H, m), 6.99-7.28 (6H, m), 7.29-7.49 (4H, m), 8.52-8.66(2H, m).

Example 2 (4-benzyl-4-hydroxypiperidin-1-yl)(3-methyl-5-(pyridin-4-yl)-1,2-oxazol-4-yl)methanone A) ethyl3-methyl-5-(pyridin-4-yl)-1,2-oxazole-4-carboxylate

To a mixture of ethyl acetoacetate (7.1 mL) and 2 M methylamine THFsolution (28 mL) was added iodine (2.2 g) under water bath, and themixture was stirred at room temperature for 3 hr. The reaction mixturewas diluted with saturated brine, and extracted with ethyl acetate/THF.The extract was dried over anhydrous sodium sulfate, and the solvent wasevaporated under reduced pressure.

To a solution of the obtained residue in toluene (60 mL) were addedtriethylamine (12 mL) and isonicotinoyl chloride (5.2 g), and themixture was stirred overnight at room temperature. The insolublematerial was filtered off, and the filtrate was concentrated underreduced pressure. The residue was diluted with saturated brine, and themixture was extracted with ethyl acetate. The extract was dried overanhydrous sodium sulfate, and the solvent was evaporated under reducedpressure.

A suspension of the obtained residue and hydroxylamine hydrochloride(2.6 g) in acetic acid (50 mL) was heated under reflux for 3 hr, and thesolvent was evaporated under reduced pressure. To the residue was addedsaturated aqueous sodium hydrogen carbonate solution, and the mixturewas extracted with ethyl acetate. The extract was dried over anhydroussodium sulfate, and the solvent was evaporated under reduced pressure.The residue was purified by silica gel column chromatography (ethylacetate/hexane) to give the title compound (0.95 g).

MS (APCI+): [M+H]⁺ 233.2.

B) 3-methyl-5-(pyridin-4-yl)-1,2-oxazole-4-carboxylic acid

To a solution of ethyl3-methyl-5-(pyridin-4-yl)-1,2-oxazole-4-carboxylate (0.95 g) in a mixedsolvent of THF (20 mL)/methanol (10 mL) was added 1N aqueous sodiumhydroxide solution (5.0 mL), and the mixture was stirred at roomtemperature for 4 hr. To the reaction mixture was added water, and themixture was washed with ethyl acetate. The obtained aqueous layer wasacidified with 1N hydrochloric acid, sodium chloride was added theretountil the mixture became saturated, and the mixture was extracted withethyl acetate. The extract was dried over anhydrous sodium sulfate, andthe solvent was evaporated under reduced pressure to give the titlecompound (0.48 g).

MS (ESI+): [M+H]⁺ 204.9.

C) (4-benzyl-4-hydroxypiperidin-1-yl)(3-methyl-5-(pyridin-4-yl)-1,2-oxazol-4-yl)methanone

A suspension of 3-methyl-5-(pyridin-4-yl)-1,2-oxazole-4-carboxylic acid(0.25 g), 4-benzyl-4-hydroxypiperidine (0.35 g), HATU (0.70 g) andtriethylamine (0.85 mL) in DMF (5.0 mL) was stirred at room temperaturefor 3 hr. The reaction mixture was diluted with water, and the mixturewas extracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane), and then purified bypreparative HPLC (C18, mobile phase: water/acetonitrile (containing 0.1%TFA)), and the obtained fraction was concentrated under reducedpressure. To the residue was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate.The extract was dried over anhydrous sodium sulfate, and the solvent wasevaporated under reduced pressure to give the title compound (0.29 g).

¹H NMR (400 MHz, DMSO-d₆) δ 1.12-1.37 (2H, m), 1.41-1.60 (2H, m), 2.23(3H, s), 2.65 (2H, brs), 3.05-3.31 (3H, m), 4.21-4.37 (1H, m), 4.54 (1H,s), 7.03-7.34 (5H, m), 7.50-7.60 (2H, m), 8.73 (2H, d, J=5.3 Hz).

Example 44-((4-hydroxy-1-(5-methyl-2-(pyridin-4-yl)benzoyl)piperidin-4-yl)methyl)benzonitrileA) tert-butyl 4-(4-bromobenzyl)-4-hydroxypiperidine-1-carboxylate

To a suspension of magnesium (2.9 g) in diethyl ether (50 mL) was addeddropwise 1,2-dibromoethane (0.90 mL) at room temperature, and thereaction mixture was vigorously stirred at room temperature for 20 min.To the reaction mixture was added dropwise a solution of 4-bromobenzylbromide (25 g) in diethyl ether (150 mL) over 30 min or more at 0° C.,and then added dropwise a solution of tert-butyl4-oxopiperidine-1-carboxylate (16 g) in diethyl ether (200 mL) over 30min or more 0° C. The reaction mixture was allowed to warm to roomtemperature, and stirred at room temperature for 3 hr. To the reactionmixture was added saturated aqueous ammonium chloride solution (200 mL),and the mixture was extracted with ethyl acetate. The extract was driedover anhydrous sodium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (12 g).

¹H NMR (400 MHz, CDCl₃) δ 1.45 (9H, s), 1.47 (2H, brs), 1.55 (2H, dd,J=12.0, 3.6 Hz), 2.71 (2H, s), 3.08 (2H, t, J=11.6 Hz), 3.85 (2H, brs),7.07 (2H, d, J=8.4 Hz), 7.44 (2H, d, J=8.4 Hz).

B) tert-butyl 4-(4-cyanobenzyl)-4-hydroxypiperidine-1-carboxylate

A mixture of tert-butyl4-(4-bromobenzyl)-4-hydroxypiperidine-1-carboxylate (35 g), K₄Fe(CN)₆(12 g), palladium(II) acetate (1.1 g), sodium carbonate (11 g),2-propanol (7.5 mL) and DMA (150 mL) was stirred at 120° C. for 12 hr.The reaction mixture was allowed to cool to room temperature, dilutedwith dichloromethane, and filtered through celite. The filtrate waswashed with water and saturated brine, dried over anhydrous magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate/hexane) to give the title compound (17 g).

¹H NMR (400 MHz, CDCl₃) δ 1.46 (9H, s), 1.47 (2H, brs), 1.55-1.56 (2H,m), 2.82 (2H, s), 3.09 (2H, t, J=11.6 Hz), 3.87 (2H, brs), 7.33 (2H, d,J=8.4 Hz), 7.62 (2H, d, J=8.4 Hz).

C) 4-(4-cyanobenzyl)-4-hydroxypiperidine hydrochloride

To a solution of tert-butyl4-(4-cyanobenzyl)-4-hydroxypiperidine-1-carboxylate (19 g) in1,4-dioxane (50 mL) was added 4.0 M HCl/1,4-dioxane solution (76 mL) at0° C., and the mixture was stirred at room temperature for 10 hr. Theresulting solid was collected by filtration, washed with ethyl acetate(100 mL) and diethyl ether (200 mL), and dried under reduced pressure togive the title compound (9.3 g).

¹H NMR (400 MHz, DMSO-d₆) δ 1.52 (2H, d, J=13.2 Hz), 1.72 (2H, td,J=13.2, 4.8 Hz), 2.83 (2H, s), 2.93-3.07 (4H, m), 5.00 (1H, s), 7.45(2H, d, J=8.0 Hz), 7.76 (2H, d, J=8.0 Hz), 8.86 (1H, brs), 9.15 (1H,brs).

D)4-((4-hydroxy-1-(5-methyl-2-(pyridin-4-yl)benzoyl)piperidin-4-yl)methyl)benzonitrile

By a method similar to that in Example 1, the title compound wasobtained.

¹H NMR (400 MHz, DMSO-d₆) δ −0.07-0.93 (1H, m), 0.96-1.14 (1H, m),1.21-1.54 (2H, m), 2.28-2.48 (4H, m), 2.55-3.08 (4H, m), 4.08-4.30 (1H,m), 4.49 (1H, d, J=10.6 Hz), 7.12-7.50 (7H, m), 7.65-7.76 (2H, m), 8.60(2H, dd, J=16.2, 5.3 Hz).

Example 8 (4-hydroxy-4-methylpiperidin-1-yl)(5-methyl-2-(pyridin-4-yl)phenyl)methanone A)1-(5-methyl-2-(pyridin-4-yl)benzoyl)piperidin-4-one

A suspension of 5-methyl-2-(pyridin-4-yl)benzoic acid hydrochloride (2.0g), piperidin-4-one hydrochloride (1.2 g), DMTMM (3.3 g) andN-methylmorpholine (2.6 mL) in DMF (30 mL) was stirred at roomtemperature for 5 hr, and then overnight at 100° C. The reaction mixturewas diluted with water, and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give the title compound (0.73 g).

MS (APCI+): [M+H]⁺ 295.1.

B) (4-hydroxy-4-methylpiperidin-1-yl)(5-methyl-2-(pyridin-4-yl)phenyl)methanone

3 M methylmagnesium bromide-diethyl ether solution (0.84 mL) was addedto a solution of 1-(5-methyl-2-(pyridin-4-yl)benzoyl)piperidin-4-one(0.37 g) in THF (10 mL) at 0° C., and the mixture was stirred overnightat room temperature. To the reaction mixture was added water at 0° C.,and the mixture was extracted with ethyl acetate. The extract was washedwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (NH, ethyl acetate/hexane) to givethe title compound (0.19 g).

¹H NMR (300 MHz, CDCl₃) δ 0.09-1.64 (8H, m), 2.42 (3H, s), 2.58-3.27(3H, m), 4.18-4.39 (1H, m), 7.09-7.56 (5H, m), 8.61 (2H, d, J=4.5 Hz).

Example 9 (4-benzyl-4-hydroxypiperidin-1-yl)(5-(pyridin-4-yl)-1,3-benzodioxol-4-yl)methanone A)(4-benzyl-4-hydroxypiperidin-1-yl)(5-bromo-1,3-benzodioxol-4-yl)methanone

A suspension of 5-bromo-1,3-benzodioxole-4-carboxylic acid (0.50 g),4-benzyl-4-hydroxypiperidine (0.59 g), HATU (1.2 g) and triethylamine(1.4 mL) in DMF (5.0 mL) was stirred overnight at room temperature. Thereaction mixture was diluted with water, and the mixture was extractedwith ethyl acetate. The extract was washed with saturated brine, anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (0.85g).

MS (APCI+): [M+H]⁺ 418.1.

B) (4-benzyl-4-hydroxypiperidin-1-yl)(5-(pyridin-4-yl)-1,3-benzodioxol-4-yl)methanone

A mixture of (4-benzyl-4-hydroxypiperidin-1-yl)(5-bromo-1,3-benzodioxol-4-yl)methanone (0.50 g), pyridine-4-boronicacid (0.22 g), sodium carbonate (0.38 g),tetrakis(triphenylphosphine)palladium(0) (0.069 g), water (0.50 mL) andDME (2.5 mL) was stirred at 150° C. for 1 hr under microwaveirradiation. The reaction mixture was diluted with water, and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine, and dried over anhydrous sodium sulfate. The solventwas evaporated under reduced pressure. The residue was purified bysilica gel column chromatography (NH, ethyl acetate/hexane) to give thetitle compound (0.85 g).

¹H NMR (300 MHz, CDCl₃) δ 0.18-0.32 (1H×½, m), 1.03-1.12 (1H×½, m),1.15-1.36 (2H, m), 1.42-1.74 (2H, m), 2.38-2.52 (1H, m), 2.72 (1H, s),2.75-2.88 (1H, m), 2.97-3.25 (2H, m), 4.40-4.54 (1H, m), 6.10 (2H, s),6.87-6.98 (2H, m), 7.02-7.16 (2H, m), 7.22-7.34 (4H, m), 7.43-7.47 (1H,m), 8.53-8.67 (2H, m).

Example 14 (4-benzyl-4-hydroxypiperidin-1-yl) (2-(pyrimidin-4-yl)phenyl)methanone A) methyl 2-(6-chloropyrimidin-4-yl)benzoate

A mixture of methyl2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (2.0 g),2,6-dichloropyrimidine (1.4 g), sodium carbonate (2.4 g),tetrakis(triphenylphosphine)palladium(0) (0.44 g), water (2.0 mL) andDME (10 mL) was stirred at 150° C. for 1 hr under microwave irradiation.The reaction mixture was diluted with water, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (0.60 g).

¹H NMR (300 MHz, CDCl₃) δ 3.75 (3H, s), 7.49-7.67 (4H, m), 7.90 (1H, dd,J=7.3, 1.3 Hz), 9.01 (1H, d, J=1.3 Hz).

B) methyl 2-(pyrimidin-4-yl)benzoate

A suspension of methyl 2-(6-chloropyrimidin-4-yl)benzoate (0.60 g),triethylamine (1.7 mL) and 10% palladium carbon (containing water (50%),0.26 g) in methanol (20 mL) was stirred at room temperature for 1 hrunder a hydrogen atmosphere. The reaction mixture was filtered, and thefiltrate was concentrated under reduced pressure. To the residue wasadded ethyl acetate, and the mixture was washed with saturated brine.The extract was dried over anhydrous sodium sulfate, and the solvent wasevaporated under reduced pressure to give the title compound (0.49 g).

MS (APCI+): [M+H]⁺ 215.2.

C) 2-(pyrimidin-4-yl)benzoic acid hydrochloride

A mixture of methyl 2-(pyrimidin-4-yl)benzoate (0.49 g), acetic acid(2.0 mL) and 6 N hydrochloric acid (10 mL) was heated under reflux for 5hr. The solvent was evaporated under reduced pressure, and the obtainedresidue was washed with ethyl acetate to give the title compound (0.45g).

MS (APCI+): [M+H]⁺ 201.2.

D) (4-benzyl-4-hydroxypiperidin-1-yl) (2-(pyrimidin-4-yl)phenyl)methanone

A suspension of 2-(pyrimidin-4-yl)benzoic acid hydrochloride (0.20 g),4-benzyl-4-hydroxypiperidine (0.24 g), HATU (0.48 g) and triethylamine(0.59 mL) in DMF (3.0 mL) was stirred overnight at room temperature. Thereaction mixture was diluted with water, and the mixture was extractedwith ethyl acetate. The extract was washed with saturated brine, anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (NH, ethyl acetate/hexane) to give the title compound(0.11 g).

¹H NMR (300 MHz, CDCl₃) δ 1.29-1.42 (2H, m), 1.50-1.78 (3H, m),2.61-2.82 (2H, m), 2.86-3.40 (3H, m), 4.37-4.60 (1H, m), 7.06-7.46 (6H,m), 7.47-7.84 (4H, m), 8.66-8.81 (1H, m), 8.85-9.27 (1H, m).

Example 16 (4-benzyl-4-hydroxypiperidin-1-yl)(5-methyl-3-(pyridin-4-yl)-1H-pyrazol-4-yl)methanone A) ethyl2-isonicotinoyl-3-oxobutanoate

A mixture of isonicotinic acid (10 g) and thionyl chloride (18 mL) wasstirred at 70° C. for 2 hr. The reaction mixture was concentrated underreduced pressure, to the residue was added dichloromethane (280 mL), andthe magnesium chloride (II) (5.1 g), pyridine (8.5 g) and ethyl3-oxobutanoate (14 g) were added thereto at 0° C. The reaction mixturewas stirred at room temperature for 3 hr, and poured into water, and themixture was extracted with dichloromethane. The extract was washed withsaturated brine, and dried over anhydrous sodium sulfate. The solventwas evaporated under reduced pressure to give the title compound (11 g).

¹H NMR (400 MHz, CDCl₃) δ 0.88 (3H, t, J=7.2 Hz), 2.46 (3H, s), 3.96(2H, q, J=6.8 Hz), 7.36 (2H, m), 8.75 (2H, brs).

B) ethyl 5-methyl-3-(pyridin-4-yl)-1H-pyrazole-4-carboxylate

To a solution of ethyl 2-isonicotinoyl-3-oxobutanoate (8.0 g) in ethanol(80 mL) was added hydrazine (1.7 g), and the mixture was stirred at roomtemperature for 1 hr, and poured into saturated aqueous sodium hydrogencarbonate solution. The mixture was extracted with ethyl acetate. Theextract was washed with saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure. The residuewas purified by silica gel column chromatography (ethyl acetate/hexane)to give the title compound (6.4 g).

¹H NMR (400 MHz, CDCl₃) δ 1.26 (3H, t, J=7.2 Hz), 2.51 (3H, s), 4.25(2H, q, J=6.8 Hz), 7.63 (2H, dd, J=1.6, 4.8 Hz), 8.66 (2H, dd, J=1.6,4.8 Hz), 11.84 (1H, brs).

C) 5-methyl-3-(pyridin-4-yl)-1H-pyrazole-4-carboxylic acid

To a solution of ethyl5-methyl-3-(pyridin-4-yl)-1H-pyrazole-4-carboxylate (3.1 g) in ethanol(20 mL) were added sodium hydroxide (8.0 g) and water (10 mL), and themixture was heated under reflux overnight. The solvent was evaporatedunder reduced pressure, the pH of the mixture was adjusted to with 2 Nhydrochloric acid, and mixture was concentrated under reduced pressure.The obtained solid was collected by filtration and washed with water togive the title compound (2.4 g).

¹H NMR (400 MHz, DMSO-d₆) δ 2.49 (3H, s), 7.68 (2H, d, J=6.0 Hz), 8.61(2H, d, J=6.0 Hz), 12.5 (1H, brs), 13.5 (1H, brs).

D) (4-benzyl-4-hydroxypiperidin-1-yl)(5-methyl-3-(pyridin-4-yl)-1H-pyrazol-4-yl)methanone

A mixture of 5-methyl-3-(pyridin-4-yl)-1H-pyrazole-4-carboxylic acid(0.47 g) and thionyl chloride (5 mL) was stirred at 70° C. for 2 hr. Thereaction mixture was concentrated under reduced pressure, and to theresidue were added dichloromethane (5.0 mL) and triethylamine (0.29 g).The mixture was added to a solution of 4-benzyl-4-hydroxypiperidine(0.36 g) in dichloromethane (5 mL), and the mixture heated under refluxfor 3 hr. The reaction mixture was poured into water, and the mixturewas extracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane), and then purifiedagain by silica gel column chromatography (NH, ethyl acetate/hexane) togive the title compound (0.070 g).

¹H NMR (300 MHz, CDCl₃) δ 1.25 (2H, s), 1.63 (2H, s), 2.31 (3H, s), 2.67(2H, s), 3.07-3.16 (1H, m), 3.30-3.34 (1H, m), 3.49 (2H, s), 4.59 (1H,d, J=12.4 Hz), 7.11 (2H, s), 7.28-7.33 (3H, m), 7.56 (2H, s), 8.61 (2H,d, J=4.8 Hz).

Example 30 (4-fluoro-2-(pyridin-4-yl)phenyl)(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)methanone A) methyl4-fluoro-2-(pyridin-4-yl)benzoate

A mixture of methyl 2-bromo-4-fluorobenzoate (1.5 g), pyridine-4-boronicacid (0.95 g), sodium carbonate (1.0 g),tetrakis(triphenylphosphine)palladium(0) (0.22 g), water (1.5 mL) andDME (9.0 mL) was stirred at 120° C. for 1 hr under microwaveirradiation. The reaction mixture was diluted with water, and themixture was extracted with ethyl acetate. The extract was washed withwater and saturated brine, and dried over anhydrous magnesium sulfate,and the solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) togive the title compound (0.89 g).

MS (APCI+): [M+H]⁺ 232.1.

B) 4-fluoro-2-(pyridin-4-yl)benzoic acid hydrochloride

A mixture of methyl 4-fluoro-2-(pyridin-4-yl)benzoate (0.88 g) and 6 Nhydrochloric acid (13 mL) was stirred at 90° C. for 18 hr. The solventwas evaporated under reduced pressure to give the title compound (0.96g).

¹H NMR (300 MHz, DMSO-d₆) δ 7.27-7.65 (2H, m), 7.82-8.26 (3H, m), 8.95(2H, d, J=6.4 Hz), 13.25 (1H, brs).

C) (4-fluoro-2-(pyridin-4-yl)phenyl)(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)methanone

A suspension of 4-fluoro-2-(pyridin-4-yl)benzoic acid hydrochloride(0.15 g), 4-(pyridin-2-ylmethyl)piperidin-4-ol (0.17 g), HATU (0.34 g)and triethylamine (0.41 mL) in DMF (2.0 mL) was stirred at roomtemperature for 2 hr. The reaction mixture was diluted with water, andthe mixture was extracted with ethyl acetate. The extract was washedwith water and saturated brine, and dried over anhydrous magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate/hexane) to give the title compound (0.16 g).

¹H NMR (300 MHz, CDCl₃) δ 0.97-1.12 (1H, m), 1.20-1.34 (1H, m),1.39-1.60 (2H, m), 2.55 (1H, s), 2.74-3.29 (4H, m), 4.40 (1H, d, J=13.2Hz), 7.01-7.23 (4H, m), 7.31-7.54 (3H, m), 7.63 (1H, t, J=7.6 Hz), 8.44(1H, brs), 8.58-8.76 (2H, m).

Example 37 (4-(4-fluorobenzyl)-4-hydroxypiperidin-1-yl)(5-methyl-2-(pyridin-4-yl)phenyl) methanone A) tert-butyl4-(4-fluorobenzyl)-4-hydroxypiperidine-1-carboxylate

To a suspension of magnesium (1.2 g) and 1,2-dibromoethane (0.11 mL) inTHF (30 mL) was added a solution of 4-fluorobenzyl chloride (6.3 mL) inTHF (10 mL) at room temperature under a nitrogen atmosphere, and themixture was stirred for 1 hr at the same temperature. The reactionmixture was cooled to −78° C., a solution of tert-butyl4-oxopiperidine-1-carboxylate (5.0 g) in THF (10 mL) was added thereto,and the mixture was allowed to warm to room temperature, and stirred for2 days. To the reaction mixture was added water at 0° C., and thensaturated aqueous potassium sodium tartrate solution, and the mixturewas extracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (NH, ethyl acetate/hexane), and recrystallizedfrom ethyl acetate/hexane to give the title compound (4.8 g).

¹H NMR (300 MHz, CDCl₃) δ 1.34-1.72 (13H, m), 2.73 (2H, s), 3.09 (2H, t,J=11.3 Hz), 3.85 (2H, d, J=9.8 Hz), 6.95-7.06 (2H, m), 7.10-7.20 (2H, m)

B) 4-(4-fluorobenzyl)-4-hydroxypiperidine hydrochloride

To a solution of tert-butyl4-(4-fluorobenzyl)-4-hydroxypiperidine-1-carboxylate (2.0 g) in ethanol(10 mL) was added 2.0 M HCl/ethanol solution (20 mL), and the mixturewas stirred at room temperature for 3 hr. The solvent was evaporatedunder reduced pressure, and the obtained solid was recrystallized fromethanol/hexane to give the title compound (1.4 g).

¹H NMR (400 MHz, DMSO-d₆) δ 1.40-1.77 (4H, m), 2.71 (2H, s), 2.86-3.16(4H, m), 4.79 (1H, s), 7.02-7.33 (4H, m), 8.83 (2H, brs).

C) (4-(4-fluorobenzyl)-4-hydroxypiperidin-1-yl)(5-methyl-2-(pyridin-4-yl)phenyl)methanone

By a method similar to that in Example 1, the title compound wasobtained.

¹H NMR (300 MHz, CDCl₃) δ 0.08-1.56 (5H, m), 2.28-2.47 (4H, m),2.51-2.82 (2H, m), 2.87-3.15 (2H, m), 4.33-4.59 (1H, m), 6.88-7.57 (9H,m), 8.52-8.75 (2H, m).

Example 44 (4-benzyl-4-hydroxypiperidin-1-yl)(2,4′-bipyridin-3-yl)methanone A) ethyl 2,4′-bipyridine-3-carboxylate

A mixture of ethyl 2-chloronicotinate (16.2 g), pyridine-4-boronic acid(12.9 g), sodium carbonate (27.8 g),tetrakis(triphenylphosphine)palladium(0) (5.04 g), water (50.0 mL) andDME (250 mL) was stirred overnight at 100° C. under a nitrogenatmosphere. The reaction mixture was diluted with water, and the mixturewas extracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (NH, ethyl acetate/hexane) to give the titlecompound (14.1 g).

¹H NMR (300 MHz, CDCl₃) δ 1.09 (3H, t, J=7.0 Hz), 4.19 (2H, q, J=7.0Hz), 7.39-7.48 (3H, m), 8.21 (1H, dd, J=7.8, 1.7 Hz), 8.66-8.74 (2H, m),8.81 (1H, dd, J=4.7, 1.7 Hz).

B) 2,4′-bipyridine-3-carboxylic acid dihydrochloride

A solution of ethyl 2,4′-bipyridine-3-carboxylate (14.1 g) in 6 Nhydrochloric acid (200 mL) was heated under reflux overnight. Thesolvent was evaporated under reduced pressure, to the obtained residuewas added toluene, and the solvent was again evaporated under reducedpressure to give the title compound (16.4 g).

MS (APCI+): [M+H]⁺ 201.1.

C) (4-benzyl-4-hydroxypiperidin-1-yl) (2,4′-bipyridin-3-yl)methanone

A suspension of 2,4′-bipyridine-3-carboxylic acid dihydrochloride (5.0g), 4-benzyl-4-hydroxypiperidine (3.9 g), HATU (10 g) and triethylamine(13 mL) in DMF (50 mL) was stirred overnight at room temperature. Thereaction mixture was diluted with water, and the mixture was extractedwith ethyl acetate. The extract was washed with saturated brine, anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (NH, ethyl acetate/hexane), and recrystallized from ethylacetate/hexane to give the title compound (3.2 g).

¹H NMR (300 MHz, CDCl₃) δ 0.06-1.74 (5H, m), 2.34-3.18 (5H, m),4.42-4.60 (1H, m), 6.98-7.15 (2H, m), 7.21-7.34 (3H, m), 7.41 (1H, dd,J=7.6, 4.9 Hz), 7.61 (1H, d, J=5.3 Hz), 7.70-7.83 (2H, m), 8.62-8.81(3H, m). mp 150-152° C.

Example 54 (4-benzyl-4-hydroxypiperidin-1-yl)(2-(pyrimidin-4-yl)pyridin-3-yl)methanone A) methyl2-(3-oxidepyrimidin-4-yl)nicotinate

A mixture of methyl 2-chloronicotinate (2.0 g), pyrimidine 1-oxide (0.95g), potassium carbonate (3.2 g), palladium(II) acetate (0.13 g),tri-tert-butylphosphine tetrafluoroborate (0.51 g), copper(I) cyanide(0.10 g) and 1,4-dioxane (20 mL) was stirred at 150° C. for 2 hr undermicrowave irradiation. The reaction mixture was diluted with ethylacetate, and filtered through celite. The filtrate was concentratedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (ethyl acetate/hexane) to give the title compound(0.48 g).

MS (APCI+): [M+H]⁺ 232.1.

B) methyl 2-(pyrimidin-4-yl)nicotinate

A suspension of methyl 2-(3-oxidepyrimidin-4-yl)nicotinate (0.28 g),triethylamine (0.84 mL) and 10% palladium carbon (containing water(50%), 0.20 g) in methanol (10 mL) was stirred at room temperature for 5hr under a hydrogen atmosphere. The reaction mixture was filtered, andthe filtrate was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) togive the title compound (0.20 g).

MS (APCI+): [M+H]⁺ 216.0.

C) 2-(pyrimidin-4-yl)nicotinic acid dihydrochloride

A mixture of methyl 2-(pyrimidin-4-yl)nicotinate (0.19 g), acetic acid(1.0 mL) and 6 N hydrochloric acid (5 mL) was heated under reflux for 5hr. The solvent was evaporated under reduced pressure to give the titlecompound (0.26 g).

MS (APCI+): [M+H]⁺ 202.1.

D) (4-benzyl-4-hydroxypiperidin-1-yl)(2-(pyrimidin-4-yl)pyridin-3-yl)methanone

A suspension of 2-(pyrimidin-4-yl)nicotinic acid dihydrochloride (0.24g), 4-benzyl-4-hydroxypiperidine (0.20 g), HATU (0.50 g) andtriethylamine (0.74 mL) in DMF (6 mL) was stirred overnight at roomtemperature. The reaction mixture was diluted with water, and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine, and dried over anhydrous sodium sulfate. The solventwas evaporated under reduced pressure. The residue was purified bysilica gel column chromatography (NH, ethyl acetate/hexane), andrecrystallized from ethyl acetate/hexane to give the title compound(0.085 g).

¹H NMR (300 MHz, CDCl₃) δ 1.27-2.00 (5H, m), 2.80 (2H, s), 3.09-3.52(3H, m), 4.43-4.67 (1H, m), 7.12-7.22 (2H, m), 7.28-7.50 (4H, m),7.61-7.75 (1H, m), 8.16-8.27 (1H, m), 8.73-9.23 (3H, m).

Example 672,4′-bipyridin-3-yl(4-(4-fluorobenzyl)-4-hydroxypiperidin-1-yl)methanone

A suspension of 2-chloronicotinic acid (0.15 g),4-(4-fluorobenzyl)-4-hydroxypiperidine hydrochloride (0.26 g), HATU(0.43 g) and triethylamine (0.66 mL) in DMF (5 mL) was stirred at roomtemperature for 4 hr. The reaction mixture was diluted with water, andthe mixture was extracted with ethyl acetate. The extract was washedwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was dissolvedin DME (5.0 mL), and pyridine-4-boronic acid (0.13 g), sodium carbonate(0.20 g), tetrakis(triphenylphosphine)palladium(0) (0.055 g) and water(1.0 mL) were added thereto, and the mixture was stirred at 140° C. for1 hr under microwave irradiation. The reaction mixture was diluted withwater, and the mixture was extracted with ethyl acetate. The extract waswashed with saturated brine, and dried over anhydrous sodium sulfate.The solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (NH, ethyl acetate/hexane),and then purified by preparative HPLC (C18, mobile phase:water/acetonitrile (containing 0.1% TFA)), and the obtained fraction wasconcentrated under reduced pressure. To the residue was added saturatedaqueous sodium hydrogen carbonate solution, and the mixture wasextracted with ethyl acetate. The extract was dried over anhydroussodium sulfate, and the solvent was evaporated under reduced pressure togive the title compound (0.21 g).

¹H NMR (300 MHz, CDCl₃) δ 0.83-1.58 (5H, m), 2.31-2.50 (1H, m),2.56-3.18 (4H, m), 4.39-4.62 (1H, m), 6.89-7.18 (4H, m), 7.42 (1H, dd,J=7.5, 4.9 Hz), 7.61 (1H, d, J=4.9 Hz), 7.69-7.86 (2H, m), 8.67 (1H, d,J=4.5 Hz), 8.71-8.83 (2H, m).

Example 704-((1-(2,4′-bipyridin-3-ylcarbonyl)-4-hydroxypiperidin-4-yl)methyl)benzonitrile

A)4-(1-((2-chloropyridin-3-yl)carbonyl)-4-hydroxypiperidin-4-yl)benzonitrileA suspension of 2-chloronicotinic acid (0.20 g),4-(4-cyanobenzyl)-4-hydroxypiperidine hydrochloride (0.32 g), HATU (0.72g) and triethylamine (0.89 mL) in DMF (4.0 mL) was stirred overnight atroom temperature. The reaction mixture was diluted with water, and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine, and dried over anhydrous sodium sulfate, and filteredthrough basic silica gel. The filtrate was concentrated under reducedpressure to give the title compound (0.45 g).

MS (APCI+): [M+H]⁺ 356.0.

B)4-((1-(2,4′-bipyridin-3-ylcarbonyl)-4-hydroxypiperidin-4-yl)methyl)benzonitrile

A mixture of4-(1-((2-chloropyridin-3-yl)carbonyl)-4-hydroxypiperidin-4-yl)benzonitrile(0.45 g), pyridine-4-boronic acid (0.19 g), sodium carbonate (0.40 g),tetrakis(triphenylphosphine)palladium(0) (0.073 g), water (0.60 mL) andDME (3.0 mL) was stirred at 150° C. for 1 hr under microwaveirradiation. The reaction mixture was diluted with water, and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine, and dried over anhydrous sodium sulfate. The solventwas evaporated under reduced pressure. The residue was purified bysilica gel column chromatography (NH, ethyl acetate/hexane) to give thetitle compound (0.27 g).

¹H NMR (300 MHz, CDCl₃) δ 0.00-1.62 (5H, m), 2.35-3.17 (5H, m),4.41-4.63 (1H, m), 7.16-7.45 (3H, m), 7.50-7.85 (5H, m), 8.65 (1H, d,J=4.9 Hz), 8.71-8.84 (2H, m).

Example 82 (4-benzyl-4-hydroxypiperidin-1-yl)(2-(1,3-oxazol-5-yl)phenyl)methanone A) methyl2-(1,3-oxazol-5-yl)benzoate

To a solution of methyl 2-formylbenzoate (15 g) and tosylmethylisocyanide (18 g) in methanol (250 mL) was added potassium carbonate (15g), and the mixture was heated under reflux for 16 hr. The reactionmixture was concentrated under reduced pressure, the residue was dilutedwith ethyl acetate, and the mixture was washed with water and saturatedbrine. The extract was dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate/petroleum ether) togive the title compound (4.0 g).

¹H NMR (300 MHz, CDCl₃) δ 3.85 (3H, s), 7.30 (1H, s), 7.40-7.50 (1H, m),7.50-7.65 (2H, m), 7.75-7.85 (1H, m), 7.94 (1H, s).

B) 2-(1,3-oxazol-5-yl)benzoic acid

To a solution of methyl 2-(1,3-oxazol-5-yl)benzoate (4.0 g) in THF (40mL) was added 2 N aqueous sodium hydroxide solution (20 mL), and themixture was stirred at room temperature stirred for 2 days. To thereaction mixture was added water, and the mixture was washed withtert-butyl methyl ether. The pH of the obtained aqueous layer wasadjusted to 2 with 2N hydrochloric acid, and the mixture was extractedwith ethyl acetate. The extract was washed with saturated brine, anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure. The residue was washed with ethyl acetate/petroleumether to give the title compound (3.3 g).

¹H NMR (400 MHz, DMSO-d₆) δ 7.45 (1H, s), 7.50-7.60 (1H, m), 7.60-7.70(2H, m), 7.70-7.80 (1H, m), 8.46 (1H, s), 13.19 (1H, brs).

C) (4-benzyl-4-hydroxypiperidin-1-yl) (2-(1,3-oxazol-5-yl)phenyl)methanone

A suspension of 2-(1,3-oxazol-5-yl)benzoic acid (0.30 g),4-benzyl-4-hydroxypiperidine (0.36 g),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.46 g),1-hydroxybenzotriazole (0.40 g) and triethylamine (0.40 g) in DMF (3 mL)was stirred at room temperature for 16 hr. The reaction mixture wasdiluted with water, and the mixture was extracted with ethyl acetate.The extract was washed with water and saturated brine, and dried overanhydrous sodium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/petroleum ether) to give the title compound (0.28 g).

MS (APCI+): [M+H]⁺ 363.2.

¹H NMR (400 MHz, CDCl₃) δ 0.90-1.05 (0.5H, m), 1.20-1.40 (2H, m),1.40-1.55 (0.5H, m), 1.55-1.65 (1.5H, m), 1.70-1.80 (0.5H, m), 2.60-2.83(2H, m), 3.00-3.30 (3H, m), 4.50-4.70 (1H, m), 7.10-7.20 (2H, m),7.20-7.25 (0.5H, m), 7.30-7.40 (4H, m), 7.40-7.50 (2.5H, m), 7.65-7.75(1H, m), 7.79 (0.5H, s), 7.89 (0.5H, s).

Example 862,4′-bipyridin-3-yl(4-(3,4-difluorobenzyl)-4-hydroxypiperidin-1-yl)methanoneA) tert-butyl 4-(3,4-difluorobenzyl)-4-hydroxypiperidine-1-carboxylate

To a suspension of magnesium (1.2 g) and 1,2-dibromoethane (0.11 mL) indiethyl ether (30 mL) was added a solution of 3,4-difluorobenzyl bromide(10 g) in diethyl ether (10 mL) at room temperature under a nitrogenatmosphere, and the mixture was stirred at the same temperature for 1hr. The reaction mixture was diluted with THF (30 mL), and cooled to−78° C. A solution of tert-butyl 4-oxopiperidine-1-carboxylate (5.0 g)in THF (10 mL) was added thereto, and the mixture was allowed to warm toroom temperature, and was stirred overnight. To the reaction mixture wasadded a small amount of 1N hydrochloric acid at 0° C. to quench thereaction. Saturated aqueous potassium sodium tartrate solution was addedthereto, and the mixture was extracted with ethyl acetate. The extractwas washed with saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure. The residuewas purified by silica gel column chromatography (NH, ethylacetate/hexane), and recrystallized from ethyl acetate/hexane to givethe title compound (4.9 g).

¹H NMR (300 MHz, CDCl₃) δ 1.37-1.68 (14H, m), 2.71 (2H, s), 3.09 (2H, t,J=11.5 Hz), 3.86 (2H, d, J=9.8 Hz), 6.90 (1H, ddd, J=6.1, 4.1, 2.3 Hz),6.97-7.18 (2H, m).

B) 4-(3,4-difluorobenzyl)-4-hydroxypiperidine hydrochloride

To a solution of tert-butyl4-(3,4-difluorobenzyl)-4-hydroxypiperidine-1-carboxylate (4.7 g) inethanol (30 mL) was added 2.0 M HCl/ethanol solution (36 mL), and themixture was stirred overnight at room temperature. The solvent wasevaporated under reduced pressure, and the obtained solid wasrecrystallized from ethyl acetate/diisopropyl ether to give the titlecompound (3.5 g).

¹H NMR (400 MHz, DMSO-d₆) δ 1.38-1.81 (4H, m), 2.72 (2H, s), 2.88-3.14(4H, m), 4.91 (1H, s), 6.97-7.16 (1H, m), 7.23-7.43 (2H, m), 8.98 (2H,brs).

C)2,4′-bipyridin-3-yl(4-(3,4-difluorobenzyl)-4-hydroxypiperidin-1-yl)methanone

A suspension of 2,4′-bipyridine-3-carboxylic acid dihydrochloride (0.30g), 4-(3,4-difluorobenzyl)-4-hydroxypiperidine hydrochloride (0.38 g),HATU (0.63 g) and triethylamine (0.77 mL) in DMF (4.0 mL) was stirred atroom temperature for 18 hr. The reaction mixture was diluted with water,and the mixture was extracted with ethyl acetate. The extract was washedwith water and saturated brine, and dried over anhydrous magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (NH, ethylacetate/hexane) to give the title compound (0.32 g).

¹H NMR (300 MHz, CDCl₃) δ 0.84-1.00 (1H, m), 1.11-1.38 (2H, m),1.43-1.60 (1H, m), 2.28-2.49 (1H, m), 2.55-2.75 (1H, m), 2.78-3.17 (3H,m), 4.41-4.62 (1H, m), 6.67-7.01 (2H, m), 7.01-7.17 (1H, m), 7.43 (1H,dd, J=7.5, 4.9 Hz), 7.62 (1H, d, J=4.5 Hz), 7.71-7.86 (2H, m), 8.67 (1H,d, J=4.9 Hz), 8.72-8.84 (2H, m).

Example 872,4′-bipyridin-3-yl(4-(2,4-difluorobenzyl)-4-hydroxypiperidin-1-yl)methanoneA) tert-butyl 4-(2,4-difluorobenzyl)-4-hydroxypiperidine-1-carboxylate

To a suspension of magnesium (1.2 g) and 1,2-dibromoethane (0.11 mL) indiethyl ether (30 mL) was added a solution of 2,4-difluorobenzyl bromide(10 g) in diethyl ether (10 mL) at room temperature under a nitrogenatmosphere, and the mixture was stirred at the same temperature for 1hr. The reaction mixture was diluted with THF (30 mL), and cooled to−78° C., and a solution of tert-butyl 4-oxopiperidine-1-carboxylate (5.0g) in THF (10 mL) was added thereto. The mixture was allowed to warm toroom temperature, and stirred overnight. To the reaction mixture wasadded a small amount of 1N hydrochloric acid at 0° C. to quench thereaction. Saturated aqueous potassium sodium tartrate solution was addedthereto, and the mixture was extracted with ethyl acetate. The extractwas washed with saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure. The residuewas purified by silica gel column chromatography (NH, ethylacetate/hexane), and recrystallized from ethyl acetate/hexane to givethe title compound (3.9 g).

¹H NMR (300 MHz, CDCl₃) δ 1.38-1.52 (11H, m), 1.56-1.73 (2H, m), 2.78(2H, d, J=1.1 Hz), 3.10 (2H, t, J=11.5 Hz), 3.86 (2H, d, J=10.2 Hz),6.76-6.90 (2H, m), 7.19 (1H, td, J=8.6, 6.6 Hz).

B) 4-(2,4-difluorobenzyl)-4-hydroxypiperidine hydrochloride

To a solution of tert-butyl4-(2,4-difluorobenzyl)-4-hydroxypiperidine-1-carboxylate (3.7 g) inethanol (30 mL) was added 2.0 M HCl/ethanol solution (28 mL), and themixture was stirred overnight at room temperature. The solvent wasevaporated under reduced pressure, and the obtained solid wasrecrystallized from ethyl acetate/diisopropyl ether to give the titlecompound (2.9 g).

¹H NMR (400 MHz, DMSO-d₆) δ 1.39-1.87 (4H, m), 2.73 (2H, s), 2.87-3.16(4H, m), 4.92 (1H, s), 7.04 (1H, td, J=8.5, 2.6 Hz), 7.18 (1H, td,J=9.9, 2.4 Hz), 7.30-7.50 (1H, m), 8.76 (1H, brs), 9.10 (1H, brs).

C)2,4′-bipyridin-3-yl(4-(2,4-difluorobenzyl)-4-hydroxypiperidin-1-yl)methanone

A suspension of 2,4′-bipyridine-3-carboxylic acid dihydrochloride (0.30g), 4-(2,4-difluorobenzyl)-4-hydroxypiperidine hydrochloride (0.38 g),HATU (0.63 g) and triethylamine (0.77 mL) in DMF (4.0 mL) was stirred atroom temperature for 18 hr. The reaction mixture was diluted with water,and the mixture was extracted with ethyl acetate. The extract was washedwith water and saturated brine, and dried over anhydrous magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (NH, ethylacetate/hexane) to give the title compound (0.30 g).

¹H NMR (300 MHz, CDCl₃) δ 0.81-1.62 (4H, m), 2.36-2.57 (1H, m),2.60-3.20 (4H, m), 4.39-4.62 (1H, m), 6.71-6.90 (2H, m), 6.95-7.20 (1H,m), 7.36-7.49 (1H, m), 7.63 (1H, brs), 7.74 (2H, brs), 8.53-8.88 (3H,m).

Example 92 (4-(4-fluorobenzyl)-4-hydroxypiperidin-1-yl)(2-(pyrimidin-4-yl)pyridin-3-yl)methanone

A suspension of 2-(pyrimidin-4-yl)nicotinic acid dihydrochloride (0.25g), 4-(4-fluorobenzyl)-4-hydroxypiperidine hydrochloride (0.22 g), HATU(0.52 g) and triethylamine (0.76 mL) in DMF (3 mL) was stirred overnightat room temperature. The reaction mixture was diluted with water, andthe mixture was extracted with ethyl acetate. The extract was washedwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (NH, ethyl acetate/hexane), andrecrystallized from ethyl acetate/hexane to give the title compound(0.050 g)

¹H NMR (300 MHz, CDCl₃) δ 1.21-1.98 (5H, m), 2.76 (2H, s), 3.10-3.50(3H, m), 4.44-4.67 (1H, m), 6.96-7.07 (2H, m), 7.09-7.20 (2H, m),7.40-7.50 (1H, m), 7.62-7.76 (1H, m), 8.23 (1H, d, J=4.9 Hz), 8.74 (1H,dd, J=4.5, 1.5 Hz), 8.81-9.23 (2H, m). mp 171-173° C.

Example 44 (4-benzyl-4-hydroxypiperidin-1-yl)(2,4′-bipyridin-3-yl)methanone A) (4-benzyl-4-hydroxypiperidin-1-yl)(2-chloropyridin-3-yl)methanone

To a mixture of 2-chloronicotinic acid (1.0 g), toluene (15 mL) and DME(5 mL) was added thionyl chloride (0.51 mL), and the mixture was stirredat 90° C. for 4 hr under a nitrogen atmosphere. The reaction mixture wasconcentrated under reduced pressure, the residue was dissolved in THF(15 mL), and triethylamine (0.97 mL) and 4-benzyl-4-hydroxypiperidine(1.1 g) were added thereto. The reaction mixture was stirred overnightat room temperature under a nitrogen atmosphere, saturated aqueoussodium hydrogen carbonate solution was added thereto, and the mixturewas extracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (1.9 g).

MS (APCI+): [M+H]⁺ 331.1.

B) (4-benzyl-4-hydroxypiperidin-1-yl) (2,4′-bipyridin-3-yl)methanone

A mixture of (4-benzyl-4-hydroxypiperidin-1-yl)(2-chloropyridin-3-yl)methanone (5.0 g),tetrakis(triphenylphosphine)palladium(0) (0.87 g), pyridine-4-boronicacid (2.2 g), sodium carbonate (4.8 g), DMF (50 mL) and water (10 mL)was stirred overnight at 100° C. under a nitrogen atmosphere. To thereaction mixture was added saturated brine, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (NH, ethyl acetate/hexane) to give the titlecompound (3.4 g). The compound was crystallized from ethylacetate/heptane to give the title compound as crystals.

¹H NMR (300 MHz, CDCl₃) δ 0.05-1.73 (5H, m), 2.34-2.53 (1H, m),2.61-3.25 (4H, m), 4.37-4.64 (1H, m), 6.96-7.16 (2H, m), 7.19-7.34 (3H,m), 7.42 (1H, dd, J=7.6, 4.9 Hz), 7.54-7.85 (3H, m), 8.60-8.83 (3H, m).mp 150° C.

Example 92 (4-(4-fluorobenzyl)-4-hydroxypiperidin-1-yl)(2-(pyrimidin-4-yl)pyridin-3-yl)methanone A) ethyl2-(1-ethoxyvinyl)nicotinate

To a mixture of ethyl 2-chloronicotinate (23 g),tributyl(1-ethoxyvinyl)tin (64 mL) and toluene (400 mL) was addedtetrakis (triphenylphosphine)palladium(0) (7.3 g), and the mixture wasstirred overnight at 80° C. under an argon atmosphere. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography (NH, ethyl acetate/hexane), and thenpurified by silica gel column chromatography (ethyl acetate/hexane) togive the title compound (27 g).

¹H NMR (300 MHz, CDCl₃) δ 1.31-1.42 (6H, m), 3.91 (2H, q, J=7.2 Hz),4.34 (2H, q, J=7.2 Hz), 4.43 (1H, d, J=2.3 Hz), 4.95 (1H, d, J=2.3 Hz),7.29 (1H, dd, J=7.9, 4.9 Hz), 7.89 (1H, dd, J=7.7, 1.7 Hz), 8.64 (1H,dd, J=4.9, 1.9 Hz).

B) ethyl 2-acetylnicotinate

To a mixture of ethyl 2-(1-ethoxyvinyl)nicotinate (27 g) and acetone(300 mL) was added 2M hydrochloric acid (370 mL), and the mixture wasstirred overnight at room temperature. The solvent was evaporated underreduced pressure, to the residue were added ethyl acetate and saturatedaqueous sodium hydrogen carbonate solution, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (15 g).

¹H NMR (300 MHz, CDCl₃) δ 1.37 (3H, t, J=7.2 Hz), 2.69 (3H, s), 4.39(2H, q, J=7.2 Hz), 7.47 (1H, dd, J=7.7, 4.7 Hz), 8.02 (1H, dd, J=7.9,1.5 Hz), 8.71 (1H, dd, J=4.9, 1.5 Hz)

C) (4-(4-fluorobenzyl)-4-hydroxypiperidin-1-yl)(2-(pyrimidin-4-yl)pyridin-3-yl)methanone

A mixture of ethyl 2-acetylnicotinate (15 g), N,N-dimethylformamidedimethyl acetal (150 mL) and acetonitrile (150 mL) was heated underreflux overnight. The reaction mixture was concentrated under reducedpressure. The obtained solid was washed with a mixed solvent of ethylacetate and hexane, and dissolved in n-butanol (150 mL) andN,N-diisopropylethylamine (150 mL). Formamidine acetate (48 g) was addedthereto, and the mixture was heated under reflux for 3 days, andconcentrated under reduced pressure. To the residue was added ethylacetate, and the mixture was washed with water and saturated brine. Tothe aqueous layer was added potassium carbonate, and the mixture wasextracted with ethyl acetate. The combined organic layers were driedover anhydrous sodium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give ethyl2-(pyrimidin-4-yl)nicotinate (5.8 g) and butyl2-(pyrimidin-4-yl)nicotinate (1.8 g), respectively. A mixture thereofwas dissolved in a mixed solvent of ethanol (100 mL) and water (20 mL),4M aqueous lithium hydroxide solution (13 mL) was added thereto, and themixture was stirred overnight at room temperature. The reaction mixturewas concentrated under reduced pressure, and the obtained residue wasdissolved in water. The pH of the solution was adjusted to 4 with 1Mhydrochloric acid, and reaction mixture was concentrated under reducedpressure. To the obtained residue were added DMF (100 mL), triethylamine(15 mL), 4-(4-fluorobenzyl)-4-hydroxypiperidine hydrochloride (6.5 g)and HATU (13 g), and the mixture was stirred overnight at roomtemperature. To the reaction mixture was added water, the insolublematerial was removed by filtration, and the filtrate was extracted withethyl acetate. The extract was washed with saturated brine, and driedover anhydrous sodium sulfate. The solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(NH, ethyl acetate/hexane), and then purified by silica gel columnchromatography (methanol/ethyl acetate), and crystallized from ethylacetate/hexane to give the title compound (2.5 g) as crystals.

¹H NMR (300 MHz, CDCl₃) δ 1.18-2.09 (5H, m), 2.77 (2H, brs), 3.08-3.63(3H, m), 4.61 (1H, d, J=12.1 Hz), 6.91-7.86 (6H, m), 8.25 (1H, brs),8.68-9.36 (3H, m). mp 174° C.

Example 102 (4-(2,4-difluorobenzyl)-4-hydroxypiperidin-1-yl)(2-(1,3-oxazol-5-yl)phenyl)methanone

A suspension of 2-(1,3-oxazol-5-yl)benzoic acid (0.15 g),4-(2,4-difluorobenzyl)-4-hydroxypiperidine hydrochloride (0.16 g), HATU(0.36 g) and triethylamine (1.1 mL) in DMF (5.0 mL) was stirredovernight at room temperature. The reaction mixture was diluted withwater, and the mixture was extracted with ethyl acetate. The extract waswashed with water and saturated brine, and dried over anhydrous sodiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate/hexane) to give the title compound (0.26 g).

¹H NMR (300 MHz, CDCl₃) δ 0.81-1.86 (5H, m), 2.67 (1H, s), 2.79 (1H, s),2.99-3.36 (3H, m), 4.60 (1H, m), 6.74-6.90 (2H, m), 7.04-7.23 (1H, m),7.27-7.52 (4H, m), 7.71 (1H, m), 7.90 (1H, s).

Example 105 (4-(2,4-difluorobenzyl)-4-hydroxypiperidin-1-yl)(2-(pyrimidin-4-yl)pyridin-3-yl)methanone

A suspension of 2-(pyrimidin-4-yl)nicotinic acid dihydrochloride (0.36g), 4-(2,4-difluorobenzyl)-4-hydroxypiperidine hydrochloride (0.42 g),HATU (0.75 g) and triethylamine (1.1 mL) in DMF (5 mL) was stirredovernight at room temperature. The reaction mixture was diluted withwater, and the mixture was extracted with ethyl acetate. The extract waswashed with saturated brine, and dried over anhydrous sodium sulfate.The solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (NH, ethyl acetate/hexane),and recrystallized from ethyl acetate/hexane to give the title compound(0.18 g).

¹H NMR (300 MHz, CDCl₃) δ 1.29-2.01 (5H, m), 2.80 (2H, s), 3.09-3.49(3H, m), 4.40-4.66 (1H, m), 6.76-6.91 (2H, m), 7.10-7.24 (1H, m),7.38-7.51 (1H, m), 7.60-7.76 (1H, m), 8.17-8.29 (1H, m), 8.70-8.78 (1H,m), 8.79-8.90 (1H, m), 8.91-9.23 (1H, m).

The compounds of the examples produced according to the above-mentionedmethod or a method analogous thereto are shown in the following tables.MS in the tables means those found.

TABLE 1 Example No. IUPAC Name Chemical Structure MS 1(4-benzyl-4-hydroxypiperidin-1- yl)(5-methyl-2-(pyridin-4-yl)phenyl)methanone

387.2 2 (4-benzyl-4-hydroxypiperidin-1-yl)(3-methyl-5-(pyridin-4-yl)-1,2- oxazol-4-yl)methanone

378.1 3 (4-hydroxy-4-(pyridin-2- ylmethyl)piperidin-1-yl)(5-methyl-2-(pyridin-4-yl)phenyl)methanone

388.2 4 4-((4-hydroxy-1-(5-methyl-2- (pyridin-4-yl)benzoyl)piperidin-4-yl)methyl)benzonitrile

412.3 5 (4-hydroxy-4-isopropylpiperidin-1- yl)(5-methyl-2-(pyridin-4-yl)phenyl)methanone

339.2 6 (4-benzyl-4-hydroxypiperidin-1- yl)(5-fluoro-2-(pyridin-4-yl)phenyl)methanone

391.2 7 (4-benzyl-4-hydroxypiperidin-1- yl)(5-chloro-2-(pyridin-4-yl)phenyl)methanone

407.1 8 (4-hydroxy-4-methylpiperidin-1- yl)(5-methyl-2-(pyridin-4-yl)phenyl)methanone

311.2

TABLE 2 Example No. IUPAC Name Chemical Structure MS 9(4-benzyl-4-hydroxypiperidin-1- yl)(5-(pyridin-4-yl)-1,3-benzodioxol-4-yl)methanone

417.1 10 (4-benzyl-4-hydroxypiperidin-1- yl)(5-methoxy-2-(pyridin-4-yl)phenyl)methanone

403.2 11 (4-benzyl-4-hydroxypiperidin-1- yl)(2-(pyridin-4-yl)phenyl)methanone

373.2 12 (4-benzyl-4-hydroxypiperidin-1- yl)(4-methyl-2-(pyridin-4-yl)phenyl)methanone

387.2 13 (4-benzyl-4-hydroxypiperidin-1- yl)(4-fluoro-2-(pyridin-4-yl)phenyl)methanone

391.3 14 (4-benzyl-4-hydroxypiperidin-1- yl)(2-(pyrimidin-4-yl)phenyl)methanone

374.2 15 (4-benzyl-4-hydroxypiperidin-1- yl)(5-methyl-2-(pyrimidin-4-yl)phenyl)methanone

388.2 16 (4-benzyl-4-hydroxypiperidin-1-yl)(5-methyl-3-(pyridin-4-yl)-1H- pyrazol-4-yl)methanone

377.2

TABLE 3 Example No. IUPAC Name Chemical Structure MS 17(4-benzyl-4-hydroxypiperidin-1- yl)(1,5-dimethyl-3-(pyridin-4-yl)-1H-pyrazol-4-yl)methanone

391.2 18 (4-benzyl-4-hydroxypiperidin-1- yl)(3-fluoro-2-(pyridin-4-yl)phenyl)methanone

391.2 19 (4-benzyl-4-hydroxypiperidin-1- yl)(2-fluoro-6-(pyridin-4-yl)phenyl)methanone

391.2 20 (5-fluoro-2-(pyridin-4- yl)phenyl)(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)methanone

392.2 21 (4-ethyl-4-hydroxypiperidin-1- yl)(5-methyl-2-(pyridin-4-yl)phenyl)methanone

325.2 22 (4-hydroxy-4-propylpiperidin-1- yl)(5-methyl-2-(pyridin-4-yl)phenyl)methanone

339.3 23 (4-hydroxy-4-(pyridin-2- ylmethyl)piperidin-1-yl)(2-(pyridin-4-yl)phenyl)methanone

374.2 24 (4-hydroxy-4-(pyridin-2- ylmethyl)piperidin-1-yl)(5-(pyridin-4-yl)-1,3-thiazol-4- yl)methanone

381.1

TABLE 4 Example No. IUPAC Name Chemical Structure MS 25(4-benzyl-4-hydroxypiperidin-1- yl)(5-(pyridin-4-yl)-1,3-thiazol-4-yl)methanone

380.2 26 (4-benzyl-4-hydroxypiperidin-1-yl)(4-(pyridin-4-yl)-1,3-thiazol-5- yl)methanone

380.2 27 (4-benzyl-4-hydroxypiperidin-1- yl)(3-methyl-2-(pyridin-4-yl)phenyl)methanone

387.2 28 (4-benzyl-4-hydroxypiperidin-1- yl)(2-(3-fluoropyridin-4-yl)phenyl)methanone

391.2 29 (2-(3-fluoropyridin-4-yl)phenyl)(4- hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)methanone

392.1 30 (4-fluoro-2-(pyridin-4- yl)phenyl)(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)methanone

392.1 31 (4-benzyl-4-hydroxypiperidin-1-yl)(2-methyl-5-(pyridin-4-yl)-1,3- thiazol-4-yl)methanone

394.2 32 (4-benzyl-4-hydroxypiperidin-1-yl)(1-methyl-4-(pyridin-4-yl)-1H- pyrazol-5-yl)methanone

377.2

TABLE 5 Example No. IUPAC Name Chemical Structure MS 33(4-hydroxy-4-(pyridin-2- ylmethyl)piperidin-1-yl)(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-5- yl)methanone

378.2 34 (4-hydroxy-4-(pyridin-2- ylmethyl)piperidin-1-yl)(2-(pyrimidin-4-yl)phenyl)methanone

375.2 35 (4-hydroxy-4-(pyridin-2- ylmethyl)piperidin-1-yl)(2-methyl-5-(pyridin-4-yl)-1,3-thiazol-4- yl)methanone

395.2 36 (4-benzyl-4-hydroxypiperidin-1- yl)(2-methyl-6-(pyridin-4-yl)phenyl)methanone

387.2 37 (4-(4-fluorobenzyl)-4- hydroxypiperidin-1-yl)(5-methyl-2-(pyridin-4-yl)phenyl)methanone

405.2 38 (4-(4-fluorobenzyl)-4- hydroxypiperidin-1-yl)(2-(pyridin-4-yl)phenyl)methanone

391.2 39 (4-(4,5-dihydro-1,3-thiazol-2- ylmethyl)-4-hydroxypiperidin-1-yl)(5-methyl-2-(pyridin-4- yl)phenyl)methanone

396.2 40 (4-(4,5-dihydro-1,3-thiazol-2- ylmethyl)-4-hydroxypiperidin-1-yl)(2-(pyridin-4- yl)phenyl)methanone

382.1

TABLE 6 Example No. IUPAC Name Chemical Structure MS 41(4-benzyl-4-hydroxypiperidin-1- yl)(5-(pyridin-4-yl)-3-(trifluoromethyl)-1H-pyrazol-4- yl)methanone

431.1 42 (4-benzyl-4-hydroxypiperidin-1-yl)(1-tert-butyl-5-(pyridin-4-yl)- 3-(trifluoromethyl)-1H-pyrazol-4-yl)methanone

487.2 43 (4-benzyl-4-hydroxypiperidin-1-yl)(2-methyl-4-(pyridin-4-yl)-1,3- thiazol-5-yl)methanone

394.2 44 (4-benzyl-4-hydroxypiperidin-l-yl)(2,4′-bipyridin-3-yl)methanone

374.2 45 ((7-endo)-7-benzyl-7-hydroxy-3-oxa-9-azabicyclo[3.3.1]non-9-yl)(2- (pyridin-4-yl)phenyl)methanone

415.2 46 (4-benzyl-4-hydroxypiperidin-1- yl)(4-fluoro-2-(pyrimidin-4-yl)phenyl)methanone

392.2 47 (4-(4-fluorobenzyl)-4- hydroxypiperidin-1-yl)(4-fluoro-2-(pyrimidin-4-yl)phenyl)methanone

410.2 48 (4-(4-fluorobenzyl)-4- hydroxypiperidin-1-yl)(2-(pyrimidin-4-yl)phenyl)methanone

392.2

TABLE 7 Example No. IUPAC Name Chemical Structure MS 49(4-(2-fluorobenzyl)-4- hydroxypiperidin-1-yl)(2-(pyridin-4-yl)phenyl)methanone

391.2 50 (4-(3-fluorobenzyl)-4- hydroxypiperidin-1-yl)(2-(pyridin-4-yl)phenyl)methanone

391.2 51 (4-(3-fluorobenzyl)-4- hydroxypiperidin-1-yl)(2-(pyrimidin-4-yl)phenyl)methanone

392.1 52 (4-(2-fluorobenzyl)-4- hydroxypiperidin-1-yl)(2-(pyrimidin-4-yl)phenyl)methanone

392.2 53 (4-benzyl-4-hydroxypiperidin-1- yl)(4,5-difluoro-2-(pyridin-4-yl)phenyl)methanone

409.1 54 (4-benzyl-4-hydroxypiperidin-1-yl)(2-(pyrimidin-4-yl)pyridin-3- yl)methanone

375.2 55 (4-benzyl-4-hydroxypiperidin-1-yl)(4,5-difluoro-2-(pyrimidin-4- yl)phenyl)methanone

410.1 56 (4,5-difluoro-2-(pyrimidin-4-yl)phenyl)(4-hydroxy-4-(pyridin-2- ylmethyl)piperidin-1-yl)methanone

411.2

TABLE 8 Example No. IUPAC Name Chemical Structure MS 57(4-benzyl-4-hydroxypiperidin-1- yl)(5-fluoro-2-(pyrimidin-4-yl)phenyl)methanone

392.1 58 (5-fluoro-2-(pyrimidin-4- yl)phenyl)(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)methanone

393.2 59 (4-benzyl-4-methoxypiperidin-1- yl)(5-methyl-2-(pyridin-4-yl)phenyl)methanone

401.2 60 (4-benzyl-4-hydroxypiperidin-1-yl)(2-methyl-4-(pyrimidin-4-yl)- 1,3-thiazol-5-yl)methanone

395.2 61 (4-hydroxy-4-(pyridin-2- ylmethyl)piperidin-1-yl)(2-methyl-4-(pyrimidin-4-yl)-1,3-thiazol-5- yl)methanone

396.2 62 (4-(4-fluorobenzyl)-4- hydroxypiperidin-1-yl)(2-methyl-4-(pyrimidin-4-yl)-1,3-thiazol-5- yl)methanone

413.1 63 (4-fluoro-2-(pyrimidin-4- yl)phenyl)(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)methanone

393.2 64 2,4′-bipyridin-3-yl(4-(2- fluorobenzyl)-4-hydroxypiperidin-1-yl)methanone

392.1

TABLE 9 Example No. IUPAC Name Chemical Structure MS 652,4′-bipyridin-3-yl(4-(3- fluorobenzyl)-4-hydroxypiperidin-1-yl)methanone

392.1 66 2,4′-bipyridin-3-yl(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1- yl)methanone

375.2 67 2,4′-bipyridin-3-yl(4-(4- fluorobenzyl)-4-hydroxypiperidin-1-yl)methanone

392.1 68 4-((4-hydroxy-1-(2-(pyrimidin-4- yl)benzoyl)piperidin-4-yl)methyl)benzonitrile

399.2 69 4-((1-(4-fluoro-2-(pyrimidin-4-yl)benzoyl)-4-hydroxypiperidin-4- yl)methyl)benzonitrile

417.1 70 4-((1-(2,4′-bipyridin-3- ylcarbonyl)-4-hydroxypiperidin-4-yl)methyl)benzonitrile

399.1 71 2-((1-(2,4′-bipyridin-3- ylcarbonyl)-4-hydroxypiperidin-4-yl)methyl)benzonitrile

399.2 72 3-((1-(2,4′-bipyridin-3- ylcarbonyl)-4-hydroxypiperidin-4-yl)methyl)benzonitrile

399.1

TABLE 10 Example No. IUPAC Name Chemical Structure MS 734-((4-hydroxy-1-((2-methyl-4- (pyrimidin-4-yl)-1,3-thiazol-5-yl)carbonyl)piperidin-4- yl)methyl)benzonitrile

420.1 74 2-((1-(4-fluoro-2-(pyrimidin-4-yl)benzoyl)-4-hydroxypiperidin-4- yl)methyl)benzonitrile

417.2 75 3-((1-(4-fluoro-2-(pyrimidin-4-yl)benzoyl)-4-hydroxypiperidin-4- yl)methyl)benzonitrile

417.1 76 (4-benzyl-4-hydroxypiperidin-1- yl)(3-(pyridin-4-yl)pyrazin-2-yl)methanone

375.2 77 2-((1-(5-fluoro-2-(pyrimidin-4-yl)benzoyl)-4-hydroxypiperidin-4- yl)methyl)benzonitrile

417.1 78 3-((1-(5-fluoro-2-(pyrimidin-4-yl)benzoyl)-4-hydroxypiperidin-4- yl)methyl)benzonitrile

417.1 79 4-((1-(5-fluoro-2-(pyrimidin-4-yl)benzoyl)-4-hydroxypiperidin-4- yl)methyl)benzonitrile

417.1 80 (4-(4-fluorobenzyl)-4- hydroxypiperidin-1-yl)(5-fluoro-2-(pyrimidin-4-yl)phenyl)methanone

410.2

TABLE 11 Example No. IUPAC Name Chemical Structure MS 81(4-(4-fluorobenzyl)-4- hydroxypiperidin-1-yl)(3-(pyridin-4-yl)pyrazin-2-yl)methanone

393.2 82 (4-benzyl-4-hydroxypiperidin-1- yl)(2-(1,3-oxazol-5-yl)phenyl)methanone

363.2 83 (4-benzyl-4-hydroxypiperidin-1- yl)(4-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methanone

377.2 84 (4-benzyl-4-hydroxypiperidin-1-yl)(3,4′-bipyridin-3′-yl)methanone

374.2 85 (4-benzyl-4-hydroxypiperidin-1- yl)(2-(pyridazin-4-yl)phenyl)methanone

374.2 86 2,4′-bipyridin-3-yl(4-(3,4- difluorobenzyl)-4-hydroxypiperidin-1-yl)methanone

410.2 87 2,4′-bipyridin-3-yl(4-(2,4- difluorobenzyl)-4-hydroxypiperidin-1-yl)methanone

410.2 88 (4-(3,4-difluorobenzyl)-4- hydroxypiperidin-1-yl)(2-methyl-4-(pyrimidin-4-yl)-1,3-thiazol-5- yl)methanone

431.1

TABLE 12 Example No. IUPAC Name Chemical Structure MS 89(4-(2,4-difluorobenzyl)-4- hydroxypiperidin-1-yl)(2-methyl-4-(pyrimidin-4-yl)-1,3-thiazol-5- yl)methanone

431.0 90 (4-(2,3-difluorobenzyl)-4- hydroxypiperidin-1-yl)(2-methyl-4-(pyrimidin-4-yl)-1,3-thiazol-5- yl)methanone

431.0 91 4-((4-hydroxy-1-((2-(pyrimidin-4-yl)pyridin-3-yl)carbonyl)piperidin- 4-yl)methyl)benzonitrile

400.2 92 (4-(4-fluorobenzyl)-4- hydroxypiperidin-1-yl)(2-(pyrimidin-4-yl)pyridin-3- yl)methanone

393.2 93 2,4′-bipyridin-3-yl(4-(2,3- difluorobenzyl)-4-hydroxypiperidin-1-yl)methanone

410.1 94 4-((4-hydroxy-1-(2-(pyridin-4- yl)benzoyl)piperidin-4-yl)methyl)benzonitrile

398.2 95 4-((1-(5-fluoro-2-(pyridin-4- yl)benzoyl)-4-hydroxypiperidin-4-yl)methyl)benzonitrile

416.1 96 4-((1-(4-fluoro-2-(pyridin-4- yl)benzoyl)-4-hydroxypiperidin-4-yl)methyl)benzonitrile

416.1

TABLE 13 Example No. IUPAC Name Chemical Structure MS 972,4′-bipyridin-3-yl(4-hydroxy-4-(4- methoxybenzyl)piperidin-1-yl)methanone

404.1 98 2, 4′-bipyridin-3-yl(4-hydroxy-4-(4-(trifluoromethoxy)benzyl)piperidin- 1-yl)methanone

458.1 99 (4-(4-fluorobenzyl)-4- hydroxypiperidin-1-yl)(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-5- yl)methanone

395.2

TABLE 14 Example No. IUPAC Name Chemical Structure MS 100(4-(4-fluorobenzyl)-4- hydroxypiperidin-1-yl)(2-(1,3-oxazol-5-yl)phenyl)methanone

381.1 101 (4-(3,4-difluorobenzyl)-4- hydroxypiperidin-1-yl)(2-(1,3-oxazol-5-yl)phenyl)methanone

399.1 102 (4-(2,4-difluorobenzyl)-4- hydroxypiperidin-1-yl)(2-(1,3-oxazol-5-yl)phenyl)methanone

399.1 103 4-((4-hydroxy-1-(2-(1,3-oxazol-5- yl) benzoyl)piperidin-4-yl)methyl)benzonitrile

388.1 104 (4-hydroxy-4-(pyridin-2- ylmethyl)piperidin-1-yl)(2-(1,3-oxazol-5-yl)phenyl)methanone

364.2 105 (4-(2,4-difluorobenzyl)-4- hydroxypiperidin-1-yl)(2-(pyrimidin-4-yl)pyridin-3- yl)methanone

411.1 106 (4-(3,4-difluorobenzyl)-4- hydroxypiperidin-1-yl)(2-(pyrimidin-4-yl)pyridin-3- yl)methanone

411.1

Formulation Example 1 (Production of Capsule)

1) compound of Example 1 30 mg 2) finely divided powder cellulose 10 mg3) lactose 19 mg 4) magnesium stearate 1 mg Total 60 mg

1), 2), 3) and 4) are mixed and filled in a gelatin capsule.

Formulation Example 2 (Production of Tablet)

1) compound of Example 1 30 g 2) lactose 50 g 3) cornstarch 15 g 4)calcium carboxymethylcellulose 44 g 5) magnesium stearate 1 g 1000tablets total 140 g

The total amount of 1), 2) and 3) and 4) (30 g) is kneaded with water,vacuum dried, and sieved. The sieved powder is mixed with 4) (14 g) and5) (1 g), and the mixture is punched by a tableting machine, whereby1000 tablets containing 30 mg of the compound of Example 1 per tabletare obtained.

Experimental Example 1: Construction of Human CH24H (CYP46) ExpressionVector

A plasmid DNA for expressing human CH24H in FreeStyle 293 cell wasproduced as follows. Using Full-Length Mammalian Gene Collection No.4819975 (Invitrogen) as a template, and the following two kinds ofsynthesis DNAs:

(SEQ ID NO: 1) 5′-GCCCCGGAGCCATGAGCCCCGGGCTG-3′ and (SEQ ID NO: 2)5′-GTCCTGCCTGGAGGCCCCCTCAGCAG-3′,PCR was performed to amplify 91-1625 bp region of human CH24H(BC022539). The obtained fragment was cloned using TOPO TA Cloning Kit(Invitrogen). The obtained fragment was subcloned to pcDNA3.1(+)digested with BamHI and XhoI to give a plasmid DNA (pcDNA3.1(+)/hCH24H)for human CH24H expression.

Experimental Example 2: Expression of Human CH24H and Preparation ofHuman CH24H Lysate

The expression of human CH24H was performed using FreeStyle 293Expression System (Invitrogen). According to the manual attached toFreeStyle 293 Expression System and using the plasmid DNA(pcDNA3.1(+)/hCH24H) for human CH24H expression constructed inExperimental Example 1, a transient expression using FreeStyle 293-Fcell was performed. After transfection, the cells were cultured withshaking at 37° C., 8% CO₂, 125 rpm for 2 days. The cells were collectedby centrifugation, and suspended in a buffer for suspension (100 mMpotassium phosphate (pH 7.4), 0.1 mM EDTA, 1 mM DTT, 20% Glycerol). Thesuspended product was disrupted by a polytron homogenizer (manufacturedby Kinematica), and centrifuged at 9000×g for 10 min, and thesupernatant was collected. The collected supernatant was cryopreserved(−80° C.) as a human CH24H lysate standard product.

Experimental Example 3: Measurement of CH24H Inhibitory Activity

For the measurement of CH24H inhibitory activity, using the human CH24Hlysate prepared in Experimental Example 2, the amount of 24-HC producedfrom cholesterol by catalysis of CH24H was measured in the presence of atest compound, and the amount was compared with that in the absence ofthe test compound. That is, a test compound solution at variousconcentrations were mixed with a reaction buffer (50 mM potassiumphosphate containing 0.1% BSA and Complete, EDTA-free protease inhibitorcocktail, pH 7.4) and human CH24H lysate. Then, [¹⁴C] cholesterol (53mCi/mmol specific activity, 15 μM) was added, and CH24H reaction wasperformed at 37° C. for hr. After completion of the reaction, aquenching solution consisting of chloroform/methanol/distillation water(2:2:1 v/v) was added, and the resulting 24-HC was extracted by shaking.The extract was applied to silica gel thin layer chromatography (ethylacetate:toluene=4:6), and the obtained ¹⁴C-24HC fraction was measuredwith BAS2500 (Fujifilm Corporation).

The inhibitory rate (%) was calculated from the ratio of radioactivityin the presence of a test compound relative to the radioactivity in theabsence of the test compound. The results are shown in the followingTables 15 and 16.

TABLE 15 Test compound Inhibitory rate (%) at 1 μM Example 1 92 Example2 90 Example 5 70 Example 9 87 Example 14 92 Example 25 94 Example 26 92Example 30 91 Example 32 92 Example 34 90 Example 39 90 Example 41 93Example 44 95 Example 54 90 Example 56 90 Example 58 84 Example 59 83Example 60 82 Example 63 82 Example 67 89 Example 70 89 Example 82 87Example 86 89 Example 87 89 Example 92 88 Example 97 87

TABLE 16 Test compound Inhibitory rate (%) at 1 μM Example 102 89Example 105 95

Experimental Example 4: Quantification Test of 24-HC

Animals used were 6-week-old female C57BL/6N mice (3 mice/group). A testcompound was suspended in a 0.5% aqueous methylcellulose [133-14255WAKO] solution (1 mg/mL). The body weight of the mice was measured, andthe solution was forcibly administered orally and repeatedly once a dayfor 3 days. At 16 hours after the third administration, half of thebrain was recovered, and the amount of 24-HC was measured.

The wet weight of the brain was measured, and the brain was homogenizedwith about 4-fold amount (0.5 mL) of saline. This solution was used as abrain extract. 24-HC in the brain extract was extracted with anacetonitrile solution (98% acetonitrile, 1.98% methanol, 0.02% formicacid), and quantified by HPLC. The average value of 24-HC amount wascalculated and the results are shown in relative values with the controlgroup as 100%. The results are shown in the following Table 17.

TABLE 17 Test compound decrease rate (%) at 10 mg/kg Example 14 67Example 30 87 Example 44 55 Example 54 64 Example 62 71 Example 67 43Example 70 60 Example 87 37 Example 92 60 Example 105 40

Experimental Example 5: Y-Maze Test Using APP/PS1 Double TransgenicMouse

Animals used were 3-month-old female APP/PS1 double transgenic mice(10-15 mice/group). A test compound was suspended in a 0.5% aqueousmethylcellulose [133-14255 WAKO] solution (1 mg/mL). The body weight ofthe mice was measured, and the solution was forcibly administered orallyand repeatedly once a day for 14 days. At 16 hours after the 13thadministration, spontaneous alternation behavior in Y-maze test wasevaluated. Using a particular arm of a Y-shaped test apparatus as thestarting point, the frequency of moving to a different arm was countedfor 5 min. The first two times of entry were excluded from the totalnumber of entry. In addition, the mice that entered less than 10 timesin total were excluded. Movement to an arm different from the arm intowhich the mouse entered last but one was considered an alternationbehavior, and the ratio to the total number of moving was calculated asa spontaneous alternation behavior rate. As comparison subjects, acontrol group (test compound-non treatment group) and a control group inwild-type mice were used. The results are shown in the following Table18.

TABLE 18 Spontaneous alternation behavior rate (%) wild-type miceAPP/PS1 double transgenic mouse Test compound control group controlgroup 10 mg/kg 30 mg/kg Example 44 68 56 71 71 Example 92 71 57 62 72

INDUSTRIAL APPLICABILITY

The compound of the present invention has a superior CH24H inhibitoryaction, which is useful as an agent for the prophylaxis or treatment ofneurodegenerative disease (e.g., Alzheimer's disease, mild cognitiveimpairment, Huntington's disease, Parkinson's disease, amyotrophiclateral sclerosis, traumatic brain injury, cerebral infarction,glaucoma, multiple sclerosis and the like), epilepsy, schizophrenia andthe like.

This application is based on patent application No. 2011-222741 filed inJapan, the contents of which are encompassed in full herein.

The invention claimed is:
 1. A method for the treatment of aneurodegenerative disease in a mammal, which comprises administering aneffective amount of a compound of formula (I),

wherein R¹ is an optionally substituted C₁₋₆ alkyl group; R² is ahydrogen atom or an optionally substituted C₁₋₆ alkyl group; R³ is anoptionally substituted 5- or 6-membered aromatic heterocyclic group;ring A is a further optionally substituted piperidine ring (thepiperidine ring is optionally bridged); and ring B is a furtheroptionally substituted 5- or 6-membered aromatic ring (X and Y areindependently a carbon atom or a nitrogen atom), or a salt thereof, incombination with a concomitant drug to the mammal, wherein theconcomitant drug excludes an antiepilepsy drug.
 2. The method of claim1, wherein the compound of formula (I) is(4-benzyl-4-hydroxypiperidin-1-yl)(2,4′-bipyridin-3-yl)methanone or asalt thereof.
 3. The method of claim 1, wherein the compound of formula(I) is2,4′-bipyridin-3-yl(4-(2,4-difluorobenzyl)-4-hydroxypiperidin-1-yl)methanoneor a salt thereof.
 4. The method of claim 1, wherein the compound offormula (I) is(4-(4-fluorobenzyl)-4-hydroxypiperidin-1-yl)(2-(pyrimidin-4-yl)pyridin-3-yl)methanoneor a salt thereof.
 5. The method of claim 1, wherein R³ is an optionallysubstituted 5- or 6-membered nitrogen-containing aromatic heterocyclicgroup.
 6. The method of claim 1, wherein R³ is a 5- or 6-memberednitrogen-containing aromatic heterocyclic group optionally substitutedby 1 to 3 halogen atoms.
 7. The method of claim 1, wherein R³ is a grouprepresented by

wherein ring C¹ is an optionally substituted 6-memberednitrogen-containing aromatic heterocycle containing at least onenitrogen atom; and ring C² is an optionally substituted 5-memberednitrogen-containing aromatic heterocycle containing at least onenitrogen atom, each of which is optionally substituted by 1 to 3 halogenatoms.
 8. The method of claim 1, wherein ring B is benzene, thiazole,isoxazole, pyrazole, pyridine or pyrazine (X and Y are independently acarbon atom or a nitrogen atom), each of which is, in addition to R³ and—C(═O)-ring A, optionally substituted by 1 to 3 substituents selectedfrom the group consisting of: (1) a halogen atom, (2) a C₁₋₆ alkyl groupoptionally substituted by 1 to 3 halogen atoms, (3) a C₁₋₆ alkoxy group,and (4) a C₁₋₆ alkylenedioxy group.
 9. The method of claim 1, whereinring B is

each of which is, in addition to R³ and —C(═O)-ring A, optionallysubstituted by 1 to 3 substituents selected from the group consistingof: (1) a halogen atom, (2) a C₁₋₆ alkyl group optionally substituted by1 to 3 halogen atoms, (3) a C₁₋₆ alkoxy group, and (4) a C₁₋₆alkylenedioxy group.
 10. The method of claim 1, wherein R² is a hydrogenatom.
 11. The method of claim 1, wherein R¹ is a C₁₋₆ alkyl groupoptionally substituted by 1 to 3 substituents selected from the groupconsisting of: (1) a C₆₋₁₄ aryl group optionally substituted by 1 to 3substituents selected from the group consisting of: (a) a halogen atom,(b) a cyano group, and (c) a C₁₋₆ alkoxy group optionally substituted by1 to 3 halogen atoms, (2) a 5- or 6-membered monocyclic aromaticheterocyclic group optionally substituted by 1 to 3 substituentsselected from the group consisting of: (a) a halogen atom, (b) a cyanogroup, and (c) a C₁₋₆ alkoxy group optionally substituted by 1 to 3halogen atoms, and (3) a 3- to 8-membered monocyclic non-aromaticheterocyclic group optionally substituted by 1 to 3 substituentsselected from the group consisting of: (a) a halogen atom, (b) a cyanogroup, and (c) a C₁₋₆ alkoxy group optionally substituted by 1 to 3halogen atoms; R² is a hydrogen atom or a C₁₋₆ alkyl group; R³ is a 5-or 6-membered nitrogen-containing aromatic heterocyclic group optionallysubstituted by 1 to 3 halogen atoms; ring A is a piperidine ring havingno substituent other than R¹, R²—O— and —C(═O)-ring B, or anoxa-9-azabicyclo[3.3.1]nonane ring having no substituent other than R¹,R²—O— and —C(═O)-ring B; and ring B is a 5- or 6-membered aromatic ringwhich is, in addition to R³ and —C(═O)-ring A, optionally substituted by1 to 3 substituents selected from the group consisting of: (1) a halogenatom, (2) a C₁₋₆ alkyl group optionally substituted by 1 to 3 halogenatoms, (3) a C₁₋₆ alkoxy group, and (4) a C₁₋₆ alkylenedioxy group.